Initial commit
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....---
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Qui comprendiamo:
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- BEH-AXO: Axon
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- BEH-PRE: Presynapse
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- BEH-VCGG: Voltage-Controlled Gated Channels
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# BEH-AXO: Container
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**Axon**: Axon does not contain specific behavior, here we comprehend it as a “cable” transporting the AP from SOMA to Presynapse. It expands BEH-PRE which can be Modulated (TUN).
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```Gen
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container: BEH-AXO
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expansion:
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- BEH-PRE ( fullness: 50x, active: 20x, emptiness: 10x )
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# modulated_by: TUN-SYN-AXO-PRE# possible/actual
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```
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# BEH-PRE: Container
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**Presynapse:** We treat each presynapse as standalone. The vesicle reserve pool is a strictly private, local resource of each individual presynaptic bouton. What is shared between synapses on the same axon are signals (neuromodulators) and metabolic resources (energy), but not the synaptic vesicles themselves. This ensures both independent computation and cooperative metabolic support within the axonal branch.
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**Tubs:**
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- Ca2+: Calcium Ion entering the Presynapse when VCGG open. They are key to check the concentration, release vescicles and modulation
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- Rrp: Readily Releasable Pool
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The Readily Releasable Pool consists of the vesicles that are "docked" and "primed" at the active zone of the synapse.
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Location: Directly touching the presynaptic membrane.
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Function: These are the first to be released when an action potential arrives.
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Characteristics: This pool is very small (usually only about 0.5% to 5% of total vesicles) and can be exhausted quickly during high-frequency firing, leading to "short-term depression" of the signal.
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- RecP: Recycling Pool
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The Recycling Pool is the next line of reinforcement.
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Location: Slightly further back from the membrane than the RRP.
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Function: These vesicles maintain release during moderate, physiological levels of stimulation.
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Characteristics: They are continuously refilled as the neuron "recycles" the membranes of used vesicles through endocytosis. This pool is larger than the RRP (roughly 5% to 20% of the total).
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- Rp: The "Reserve Pool" (The true RP)
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In many textbooks, RP specifically stands for the Reserve Pool.
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Location: The bulk of the vesicles held further back in the terminal, often tethered by a protein called synapsin.
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Function: These are only mobilized during intense, prolonged stimulation once the RRP and Recycling pools are depleted.
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Characteristics: This makes up the vast majority of the vesicles (up to 80% or 90%).
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- Nt: Neuro Transmitter, released in the synapse by the vescicles
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- TagRelease: forse non serve, ma indica il rilascio di NT da parte di una syn.
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**Behaviors**:
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L'idea e' che:
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- Fast
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-- i VCGG si aprano all'arrivo di un AP dal SOMA. Il numero dei VCGG presenti e' stato modulato (TUN) in una fase di non attivita' della presynapse
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-- I VCGG fanno entrare Ca2+ che ne aumenta la concentrazione
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-- ad un certo livello di concentrazione, viene liberata una vescica, se ci sono Rrp disponibili. La vescica libera xxx Nt nella sinsapsi
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- Medium
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-- clearance dei Ca2+ che depolarizza la Presinapsi
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-- riciclo delle vesciche, prendendole dalla Sinapsi e mettenedole dentro a RecP
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- Slow
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-- riempimento vesciche di Nt e mettendole dentro Rp
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-- spostamento da Rp a RecP
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```Gen
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container: BEH-PRE
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expansion:
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- BEH-PRE-VGCC ( fullness: 10x, active: 5x, emptiness: 2x )
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# modulated_by: TUN-PRE-VGCC # possible/actual
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tub_local:
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- Ca2+ ( fullness: 60x, active: 30x, emptiness: 0x )
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# modulated_by: DEV-PRE-CA2+FULL # Full
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- Rrp ( fullness: 30x, active: 15x, emptiness: 0x )
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# modulated_by: DEV-PRE-RRP-FULL # Full
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- Rp ( fullness: 30x, active: 15x, emptiness: 0x )
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# modulated_by: DEV-PRE-RRP-FULL # Full
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- TagRelease ( fullness: 1x, active: 0x, emptiness: 0x )
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- CaTraces ( fullness: 50x, active: 0x, emptiness: 0x )
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tub_intricated:
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- Nt ( contained_by: BEH-SYN ) # intricated name (from BEH-SYN)
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```
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## IntegrateCa2+: Context
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Qui verifichiamo il livello di CA2+ nella presynapse. I comportamenti nella presinapsi dipendo tutti da questa concentrazione, sia quelli immediati di rilascio NT da vescicles che quelli di modulazione.
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***Tens Milliseconds Time Scale***
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```Gen
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context: IntegrateCa2+
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contained_by: BEH-PRE
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in_context: Fixed
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rf: ( active: 60x )
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condition: (Ca2+ empty)
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out_context: CaEmpty
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condition: NOT (Ca2+ empty) AND NOT (Ca2+ full)
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out_context: CaMedium
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condition: (Ca2+ full)
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out_context: CaFull
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```
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## VescicleRelease: Episode
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Il rilascio di NT avviene solo se Ca+ FULLNESS? Ovviamente se ci sono Vesciche. O dipende da altro? Cioe’ cosi’ rilascerebbe tutte le vesciche se c’e’ fullness. Dovremmo mettere un tag, o una discesa improvvisa di Ca+ al release di una vescica. Perche’ potremmo avere il caso che i VGGC sia talmente tanti da far entrare tanto calcio da far si che la prima vescica consumi CA ma non abbastanza da andare sotto FULLNESS
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Rilascio di NT: Geneosoficamente dovremmo aprire un nuovo contesto che rilascia ad un RF veloce un NT alla volta quando sei nel contesto di rilascio vescica, perche’ Geneosoficamente possiamo solo creare/distruggere blocco. Ma forse possiamo mettere un floor per efficienza: rilascio di una vescica == rilascio 1000 NT? Anche se poi l’Astrocita deve fare un uptake NT per NT?
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***Time: t = 0.4-1.5 ms after AP arrival***
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- Ca²⁺microdomain > 10-25 µM
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- Vesicle in RRP (docked & primed)
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- Release latency: 0.1-1.0 ms after Ca²⁺ threshold reached
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- Release synchrony: Multiple vesicles can release simultaneously
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```Gen
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episode: VescicleRelease
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contained_by: BEH-PRE
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in_context: CaFull
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rf: ( active: 6x )
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hypothesis: (Ca2+ full) AND NOT (Rrp empty)
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action: [Rrp decrease, Nt increase, Ca2+ decrease,
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TagRelease increase]
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trace: None
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```
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## Ca+ClearenceSlow: Episode
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Svuotiamo a due velocita’. Il context (Check Ca+ concentration) e’ determinato a epoca piu’ lunga, tanto ci vuole qualche giro per fare entrare i primi Ca+
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Le tracce lasciate servono alla modulazione
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***Time: t = 1-50 ms after influx***
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```Gen
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episode: Ca+ClearenceSlow
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contained_by: BEH-PRE
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in_context: CaMedium
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rf: ( active: 6x )
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hypothesis: NOT (Ca+ empty) AND NOT (Ca+ full)
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action: [Ca+ decrease, CaTraces Increase]
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trace: None
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```
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## Ca+ClearenceFast: Episode
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Qui l'idea oltre che a fare clearance e' anche quella di lasciare tracce su che livello di Ca2+ c'e' stato durante gli episodi. Un livello medio lascia meno tracce di un livello alto, e questo serve a ragionare sulla modulazione.
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Clearance mechanisms (in order of speed):
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- Fast buffers (calbindin, parvalbumin): <1 ms
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- Plasma membrane Ca²⁺ ATPase (PMCA): 10-100 ms
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- Na⁺/Ca²⁺ exchanger (NCX): 10-100 ms
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- Mitochondrial uptake: 10-1000 ms
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- Endoplasmic reticulum uptake: 100-1000 ms
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- Residual Ca²⁺: 0.1-0.5 µM persists for 10-1000 ms*
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```Gen
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episode: Ca+ClearenceFast
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contained_by: BEH-PRE
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in_context: CaFull
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rf: ( active: 1x )
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condition: (Ca2+ full)
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action: [Ca2+ decrease, CaTraces Increase]
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trace: None
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```
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```Gen
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episode: Ca+ClearenceMedium
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contained_by: BEH-PRE
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in_context: CaMedium
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rf: ( active: 1x )
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hypothesis: NOT (Ca2+ full) AND NOT (Ca2+ empty)
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action: [Ca2+ decrease, CaTraces Increase]
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trace: None
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```
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## STP - Pr Upregulation: Observable
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**Observed behavior**
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Upregulation (Facilitation): Residual Ca²⁺ from previous spikes increases P_r for next release
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***Timing: > 10 ms***
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## STD - Pr Downregulation: Observable
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**Observed behavior**
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Downregulation (Depression): High-frequency firing depletes readily releasable vesicle pool, decreasing P_r
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***Timing: > 10 ms***
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## VesciclesRecycling: Episode
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Dobbiamo capire se lasciare il recicling RecP oppure avere solo un Rp, almeno al primo giro di comprensione, per semplificare.
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Sequential steps:
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- Endocytosis (clathrin-mediated, kiss-and-run, bulk)
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- Vesicle re-acidification (v-ATPase)
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- Neurotransmitter reloading (vesicular transporters)
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- Priming (SNARE assembly, docking)
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- Return to RRP
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- Recycling rate: Limited by ATP availability
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***Time: t = 10 ms - 10 s (depending on activity)***
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```Gen
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episode: VesciclesRecycling
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contained_by: BEH-PRE
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in_context:
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rf: ( fullness: 10x, active: 5x, emptiness: 2x )
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# si parte con active, poi viene modulato
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# modulated_by: DEV-PRE-VesciclesRecycling-RF
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hypothesis:
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```
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## VescicleFromRPtoRRP-Slow: Episode
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Superpriming requires ATP for phosphorylation reactions and for molecular motors that move vesicles. If the reserve pool is depleted or ATP is low, the superpriming "conveyor belt" has nothing to feed into the RRP. (Astrocyte)
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Tracce? non ci sono abbastanza RP, lascio tracce per la modulazione UP, devo capire modulazione DOWN
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From The Reserve Pool and Recently Endocytosed Vesicles
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***Seconds-Minutes Time Scale***
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```Gen
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episode: VescicleFromRPtoRRP-Slow
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contained_by: BEH-PRE
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in_context: CaEmpty
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rf: ( active: 30x )
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hypothesis: NOT (RP empty)
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action: [RP decrease, RRP increase]
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trace: None
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```
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## VescicleFromRPtoRRP-Medium: Episode
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***Seconds-Minutes Time Scale***
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```Gen
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episode: VescicleFromRPtoRRP-Medium
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contained_by: BEH-PRE
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in_context: CaMedium
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rf: ( active: 15x )
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hypothesis: NOT (RP empty)
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action: [RP decrease, RRP increease]
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trace: None
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```
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## VescicleFromRPtoRRP-Fast: Episode
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***Seconds-Minutes Time Scale***
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```Gen
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episode: VescicleFromRPtoRRP-Fast
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contained_by: BEH-PRE
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in_context: CaFull
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rf: ( active: 5x )
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hypothesis: NOT (RP empty)
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action: [RP decrease, RRP increase]
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trace: None
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```
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## VesiclesFillingRP: Episode
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Qui riempiamo le vesciche. Fino ad un numero massimo, che viene modulato in DEV
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***Seconds-Minutes Time Scale***
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```Gen
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episode: VesiclesFillingRP
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contained_by: BEH-PRE
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in_context: AwayFromSpike
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rf: ( fullness: 100x, active: 60x, emptiness: 30x )
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# modulated_by: DEV-PRE-VesiclesFillingRP-RF # RF
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hypothesis:
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```
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# BEH-PRE-VGCC: Container
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**Voltage Gated Ion Channels**: When an AP arrives from the SOMA, VCGG are opened and they let in CA2+ initiating the possible release of NT from the vescicles. In theory each RRP has its own VCGG nearby. We do not comprehend this, but consider VCGG shared between all the RPP of the presynapse (we impose a floor)
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```Gen
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container: BEH-PRE-VGCC
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tub_intricated:
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- Ca2+ ( contained_by: BEH-PRE )
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context_intricated:
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- AP ( contained_by: BEH-SOMA )
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```
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## VgccOpen: Episode
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Auto-inhibition? Ca²⁺ binding to calmodulin on VGCC. 5-50 ms
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SK Channels: non comprendiamo i K+ CHannels che si aprono quando entra Ca+ e servono a ripolazzare la presinapsi per chiudere i VGCC. Il tutto viene compreso come contestualizzazione AP.
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***Time: t = 0 ms***
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- AP Arrives
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- Trigger: Depolarization from axon hillock
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- Mechanism: Na⁺/K⁺ voltage-gated channel cascade
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- State: Terminal depolarizes from -70 mV to +30 mV
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- Duration: \~1 ms
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***Time: t = 0.2-0.5 ms after AP arrival***
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- VGCC Open
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- Trigger: Membrane depolarization > -40 mV
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- Open probability: \~0.3-0.8 during AP peak
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- Open duration: \~0.5-2 ms
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- Ca2+ Influx
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***Time: t = 0.3-1 ms after AP arrival***
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- Ca²⁺ source: Extracellular (1.2 mM) → intracellular (50 nM baseline)
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- Influx rate: \~3000-10000 Ca²⁺ ions per VGCC per ms
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- Microdomain formation:
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- Within 20 nm of VGCC: 10-100 µM
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- At vesicle release site: 10-25 µM threshold for release
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- Rise time: <100 µs
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- Diffusion-limited spread: \~100-200 nm radius
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```Gen
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episode: VgccOpen
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contained_by: BEH-VGCC
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in_context: AP
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rf: ( active: 1x )
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hypothesis: NOT (Ca2+ full)
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action: [Ca2+ increase]
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trace: None # Se Ca+FULLNESS, lascio tracce di overflow per modulazione DOWN, da capire UP
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```
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@@ -0,0 +1,116 @@
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Qui comprendiamo:
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- BEH-BD: Dendritic Branch
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- BEH-POST: Postsynapsis
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- BEH-POST-AMPA: AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors)
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# BEH-BD: Container
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**Dendritic Branch**: In questa prima fase, non consideriamo lo spike dendritico come comportamento. Questo limita molto il modello, perche' equipara tutte le Postsinapsi sui tre branch dendritici e non permette di fare in maniera che ad esempio due branch contestualizzino (base activity) e uno faccia scattare il threshold per lo spike somatico.
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Qui BEH-DB espande solo i BEH-POST, e' un cavo di collegamento come l'assone
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```Gen
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Container: BEH-BD
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expansion:
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- BEH-POST ( fullness: 50x, active: 20x, emptiness: 10x )
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# modulated_by: TUN-SYN-BD-POST possible/actual
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```
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## BEH-POST: Container
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```Gen
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container: BEH-POST
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expansion:
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- BEH-POST-AMPA ( fullness: 10x, active: 5x, emptiness: 2x )
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# modulated_by: TUN-POST-IC # possible/actual
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tub_local:
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- Ca2+ ( fullness: 60x, active: 30x, emptiness: 0x )
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# modulated_by: DEV-POST-???-FULL # Full
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- Nox ( fullness: 100x, active: 20x, emptiness: 0x ) # Nitric Oxide (NO): A gas that diffuses freely.
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- Ecb ( fullness: 100x, active: 20x, emptiness: 0x ) # Endocannabinoids (e.g., 2-AG)
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tub_intricated:
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- Nt ( contained_by: BEH-SYN )
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- bAp ( contained_by: BEH-SOMA )
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```
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### Context
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```Gen
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context: captureNt
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contained_by: BEH-POST
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in_context: Fixed
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rf: ( active: 10x )
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condition: (Nt full) AND NOT (bAp)
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out_context: NtCaptured
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```
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### Episode
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### BEH-POST-AMPA: Container
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```Gen
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container: BEH-POST-AMPA
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tub_intricated:
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- Nt ( contained_by: BEH-SYN )
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context_intricated:
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- bAp ( contained_by: BEH-SOMA )
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```
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#### AmpaOpen: Episode
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- Timing: < 1 ms
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- InContext: Glutamate > FULLNESS
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- OutContext: AMPA receptor opening
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- Consequence: Na⁺ influx
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- Consequence: addition to local depolarization (EPSP) from AMPA activation
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```Gen
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episode: AmpaOpen
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contained_by: BEH-POST-AMPA
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in_context: NtCapured
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rf: ( active: 1x )
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hypothesis: NOT (Ca2+ full)
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action: [Ca2+ increase]
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trace: None # Se Ca+FULLNESS, lascio tracce di overflow per modulazione DOWN, da capire UP
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```
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### Depolarization by bAP
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||||
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Da ricordare i Dendritic VCGG che si aprono facendo entrare Ca2+ all'arrivo di bAP. In teoria abbiamo 3 Ion Channel.
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- Timing: > 1 ms
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- InContext: bAP backpropagating action potential
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- Consequence: addition to local depolarization (EPSP) from bAP
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### Mg²⁺ NMDA unblock
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||||
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- Timing: > 1 ms
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- InContext: local depolarization (EPSP) > FULLNESS (requires depolarization > -40mV)
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- OutContext: NMDA Mg²⁺ unblock
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### Full Ca+ influx by NDMA
|
||||
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||||
- Timing: < 1 ms
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||||
- InContext: NMDA Mg²⁺ unblock
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||||
- Consequence: Na⁺ influx
|
||||
- Consequence: addition to local depolarization (EPSP) from Full NMDA activation
|
||||
|
||||
### Upregulation: Observable
|
||||
|
||||
- Upregulation: Depolarization relieves NMDA Mg²⁺ block → Ca²⁺ influx amplification
|
||||
|
||||
### Downregulation: Observable
|
||||
|
||||
- Downregulation: AMPA desensitization acts as low-pass filter
|
||||
|
||||
##
|
||||
@@ -0,0 +1,64 @@
|
||||
# BEH-SOMA: Container
|
||||
|
||||
```Gen
|
||||
container: BEH-SOMA
|
||||
|
||||
expansion:
|
||||
- BEH-SOMA-VCGG ( fullness: 50x, active: 20x, emptiness: 10x )
|
||||
# modulated_by: TUN-SOMA-VCGG # possible/actual
|
||||
|
||||
tub_intricated:
|
||||
- SpikeTrainTraces ( contained_by: TUN-N )
|
||||
```
|
||||
|
||||
## Context
|
||||
|
||||
Qui mettiamo lo spike Dendritico. Sempre se vogliamo comprenderlo.
|
||||
|
||||
```Gen
|
||||
context: ???...
|
||||
contained_by: BEH-SOMA
|
||||
|
||||
in_context: Fixed
|
||||
rf: 60x
|
||||
|
||||
condition:
|
||||
activate: xxx
|
||||
```
|
||||
|
||||
## Episode
|
||||
|
||||
```Gen
|
||||
episode: ??
|
||||
contained_by: BEH-SOMA
|
||||
|
||||
in_context: xxx
|
||||
rf: ( active: 1x )
|
||||
|
||||
hypothesis:
|
||||
action:
|
||||
trace: None
|
||||
```
|
||||
|
||||
## BEH-SOMA-VCGG: Container
|
||||
|
||||
```Gen
|
||||
container: BEH-SOMA-VCGG
|
||||
|
||||
```
|
||||
|
||||
### Episode
|
||||
|
||||
```Gen
|
||||
episode: ??
|
||||
contained_by: BEH-VCGG
|
||||
|
||||
in_context: xxx
|
||||
rf: ( active: 1x )
|
||||
|
||||
hypothesis:
|
||||
action:
|
||||
trace: None
|
||||
```
|
||||
|
||||
##
|
||||
+204
@@ -0,0 +1,204 @@
|
||||
# DEV-N: Modulator
|
||||
|
||||
Neuron Development - LTP-LTD Behavior:
|
||||
|
||||
Il DEV-N lavora durante Night a tempi lunghi rispetto a BEH-N. In pratica cambia la forma delle possibilita’ di BEH-N.
|
||||
|
||||
Il DEV contiene quei behavior di modulazione che cambiano la somma (fullness + active). La modulazione DEV aumenta/diminuisce (fullness + active). Ovvero c’e’ creazione di nuova “forma” di possibilita’.
|
||||
|
||||
This is critical for long-term presynaptic changes. The postsynaptic cell, upon detecting specific activity patterns (like those for LTP/LTD), releases chemical signals that travel backwards to the presynaptic terminal, instructing it to change.
|
||||
|
||||
- For Presynaptic Strengthening (e.g., un LTP):
|
||||
- Nitric Oxide (NO): A gas that diffuses freely. During postsynaptic LTP induction (strong NMDAR activation), neuronal NO synthase (nNOS) is activated. NO diffuses into the presynaptic terminal and activates soluble guanylyl cyclase (sGC), raising cGMP levels. This enhances vesicle release via PKG, contributing to presynaptic LTP.
|
||||
- Endocannabinoid-Mediated LTP (eLTP): In some synapses, a postsynaptic depolarization triggers production of endocannabinoids (e.g., 2-AG). These bind to presynaptic CB1 receptors, but surprisingly, can initiate a signaling cascade (involving cAMP/PKA) that increases Pr for a long period.
|
||||
- Neurotrophins (BDNF): Released from the postsynapse in an activity-dependent manner. Presynaptic TrkB receptors activate pathways (PI3K, MAPK) that enhance vesicle docking and Pr.
|
||||
- For Presynaptic Weakening (e.g., LTD):
|
||||
- Classical Endocannabinoid-Mediated LTD (eCB-LTD): More common. Moderate postsynaptic activity (mGluR activation or moderate Ca²⁺ rise) triggers 2-AG release. 2-AG binds presynaptic CB1 receptors, which inhibit VGCCs and directly inhibit the release machinery via Gi/o protein signaling, reducing Pr for a long time.
|
||||
- Other Lipid Mediators (like LPA) can also act as retrograde signals for depression.
|
||||
|
||||
Augmentation:
|
||||
|
||||
- Calcium-sensing proteins (Munc13) alter release probability (1-10s range). How?
|
||||
|
||||
Upregulation:
|
||||
|
||||
- NO/BDNF activates cascades that increase P_r, promote synaptic growth (facilitates LTP). How?
|
||||
- VGCC TUN
|
||||
- Potassium channel modulation ??
|
||||
|
||||
Downregulation:
|
||||
|
||||
- eCBs bind CB1 receptors, inhibit VGCCs, activate K⁺ channels → profound decrease in P_r (DSE/DSI - depolarization-induced suppression)
|
||||
- CB1 receptor activation (by eCBs)
|
||||
- Retrograde BDNF (brain-derived neurotrophic factor)
|
||||
|
||||
> Night Time Scale
|
||||
|
||||
```Gen
|
||||
modulator: DEV-N
|
||||
contained_by: N
|
||||
```
|
||||
|
||||
## DEV-RF: Modulator
|
||||
|
||||
Perche’ mettiamo RF in DEV e non in TUN?
|
||||
|
||||
```Gen
|
||||
modulator: DEV-RF
|
||||
contained_by: DEV-N
|
||||
```
|
||||
|
||||
### DEV-PRE-VesciclesRecycling-RF: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: DEV-PRE-VesciclesRecycling-RF
|
||||
contained_by: DEV-RF
|
||||
|
||||
modulates: BEH-PRE/episode/VesciclesRecycling
|
||||
# each BEH-PRE is modulated!
|
||||
|
||||
tub_dev:
|
||||
- fulMod ( fullness: None, active: rf/fullness, emptiness: 0x )
|
||||
- actMod ( fullness: None, active: rf/active, emptiness: 0x )
|
||||
|
||||
# qui stiamo modulando l'active di RF mantenendolo fra fullness e
|
||||
# emptiness dichiarato in VesciclesRecycling
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
- Nox ( contained_by: BEH-POST )
|
||||
- Ecb ( contained_by: BEH-POST )
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
#### Episode
|
||||
|
||||
### DEV-PRE-VesiclesFillingRP-RF: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: DEV-PRE-VesiclesFillingRP-RF
|
||||
contained_by: DEV-RF
|
||||
|
||||
modulates:
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
- Nox ( contained_by: BEH-POST )
|
||||
- Ecb ( contained_by: BEH-POST )
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
#### Episode
|
||||
|
||||
### DEV-PRE-LactateAtp-RF: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: DEV-PRE-LactateAtp-RF
|
||||
contained_by: DEV-RF
|
||||
|
||||
modulates:
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
- Nox ( contained_by: BEH-POST )
|
||||
- Ecb ( contained_by: BEH-POST )
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
#### Episode
|
||||
|
||||
## DEV-FULL: Modulator
|
||||
|
||||
Perche’ mettiamo Full in DEV e non in TUN?
|
||||
|
||||
```Gen
|
||||
modulator: DEV-FULL
|
||||
contained_by: DEV-N
|
||||
```
|
||||
|
||||
### DEV-PRE-CA2+-FULL: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: DEV-PRE-CA2+-FULL
|
||||
contained_by: DEV-FULL
|
||||
|
||||
modulates: BEH-PRE/tub/Ca2+ # this is the tub whose "full" must be modulated
|
||||
|
||||
tub_dev:
|
||||
- fullMod ( fullness: 100x, active: Ca2+/fullness, emptiness: 50x ) # Ca2+Full "contains" a number of blocks equal to the current Full.
|
||||
# qui stiamo modulando la fullness di Ca2+, associandola ad
|
||||
# active di fullMod. Cambiando active di fullMod,
|
||||
# si cambia la fullness di Ca2+
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
- Nox ( contained_by: BEH-POST )
|
||||
- Ecb ( contained_by: BEH-POST )
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
***Tens Milliseconds Time Scale***
|
||||
|
||||
```Gen
|
||||
context: CheckPreTubCa2+
|
||||
|
||||
contained_by: DEV-PRE-FULL-CA2+
|
||||
in_context: Fixed
|
||||
rf: 60x
|
||||
|
||||
condition: ( empty )
|
||||
out_context: DecreaseFull
|
||||
|
||||
condition: NOT ( empty ) AND NOT ( Ca2+ full )
|
||||
out_context: Nothing
|
||||
|
||||
condition: ( full)
|
||||
out_context: IncreaseFull
|
||||
```
|
||||
|
||||
#### Episode
|
||||
|
||||
```Gen
|
||||
episode: VgccOpen
|
||||
contained_by: DEV-PRE-FULL-CA2+
|
||||
|
||||
in_context: DecreaseFull
|
||||
rf: 1x
|
||||
|
||||
hypothesis: NOT ( full ) AND NOT ( empty )
|
||||
action: [ increase, decrease]
|
||||
trace: None
|
||||
```
|
||||
|
||||
### DEV-PRE-RRP-FULL: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: DEV-PRE-RRP-FULL
|
||||
contained_by: DEV-FULL
|
||||
|
||||
modulates: BEH-PRE/tub/Rrp # this is the tub whose "full" must be modulated
|
||||
|
||||
tub_dev:
|
||||
- fullMod ( fullness: 100x, active: Rrp/fullness, emptiness: 50x ) # RrpFull "contains" a number of blocks equal to the current Full.
|
||||
# qui stiamo modulando la fullness di Rrp, associandola ad
|
||||
# active di fullMod. Cambiando active di fullMod,
|
||||
# si cambia la fullness di Rrp
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
- Nox ( contained_by: BEH-POST )
|
||||
- Ecb ( contained_by: BEH-POST )
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
#### Episode
|
||||
+55
@@ -0,0 +1,55 @@
|
||||
# N: Comprehension
|
||||
|
||||
Neuron Comprehension: Nel folder Appunti ci sono i comportamenti osservabili, dai quali siamo partiti, riducendo notevolmente in questa prima fase.
|
||||
|
||||
```Gen
|
||||
comprehension: N
|
||||
|
||||
include:
|
||||
- BEH-AXO.md
|
||||
- BEH-SOMA.md
|
||||
- BEH-POST.md
|
||||
- TUN-N.md
|
||||
- DEV-N.md
|
||||
|
||||
expansion:
|
||||
- BEH-N ( active: 1x )
|
||||
|
||||
tub_intricated:
|
||||
- DevPossible ( contained_by: BEH-ORG )
|
||||
# qui e' l'organismo che va a dormire (Ipotalamo)
|
||||
```
|
||||
|
||||
## IntegrateBehTunDevPossibility: Context
|
||||
|
||||
Alternanza BEH-N e TUN-N durante il giorno e DEV-N notte. Influenzata da intricazioni con l’ipotalamo che si occupa della fatica organismica. L’alternanza dei comportamenti in BEH-N e TUN-N, invece, e’ gestita in TUN-N.
|
||||
|
||||
```Gen
|
||||
context: IntegrateBehTunDevPossibility
|
||||
|
||||
contained_by: N
|
||||
in_context: Fixed
|
||||
rf: 60x
|
||||
|
||||
condition: NOT ( DevPossible Full ) # Day
|
||||
activate: BEH-N # la disattivazione e' la non attivazione
|
||||
activate: TUN-N
|
||||
|
||||
condition: ( DevPossible Full ) # Night
|
||||
activate: DEV-N
|
||||
```
|
||||
|
||||
## BEH-N: Container
|
||||
|
||||
**Neuron Behavior** (directly observable, excluding TUN e DEV).
|
||||
|
||||
Questo container serve solo ad espandere AXO, SOMA e DB.
|
||||
|
||||
```Gen
|
||||
container: BEH-N
|
||||
|
||||
expansion:
|
||||
- BEH-AXO ( active: 1x )
|
||||
- BEH-SOMA ( active: 1x )
|
||||
- BEH-DB ( active: 3x )
|
||||
```
|
||||
@@ -0,0 +1,8 @@
|
||||
Qui mettiamo le spiegazioni su come funziona l’espressione Gen.
|
||||
|
||||
Il neurone è il concetto che vogliamo comprendere. Partiamo dalla comprensione per espandere i concetti contenuti in N. L’espansione e’ anche di numerosita’ (ad esempio BEH-N espande 3 BEH-BD. Accanto all’espansione dei concetti aggiungiamo la modulabilita’ riferita a ciascun concetto (per quelli che scegliamo di voler modulare). In definitiva la comprensione risulta essere un’eterarchia e non una semplice gerarchia.
|
||||
|
||||
- Per **Comprehension** intendiamo Behavior “diretti”, piu’ DEV e TUN. L’unica comprehension in questo caso e’ N.
|
||||
- Per **Container** intendiamo SOLO contenitore di behavior “diretti” esclusi i behavior di modulazione che mettiamo in **Modulator**
|
||||
|
||||
---
|
||||
+267
@@ -0,0 +1,267 @@
|
||||
# TUN-N: Modulator
|
||||
|
||||
MTP-MTD Behavior:
|
||||
|
||||
Il TUN-N assieme a BEH-N sono entrambi attivi durante Day. TUN sente la stasi di BEH-N, quando e’ lontano da uno spiketrain, e contestualizza i comportamenti di TUN.
|
||||
|
||||
Il TUN contiene quei behavior di modulazione che non cambiano la somma (fullness + active). La modulazione TUN sposta da fullness a active e viceversa. Ovvero non c’e’ creazione di nuove “forma” di possibilita’. Nel caso di SYN, lo spostamento e’ da possible a “a disposizione” di SYN.
|
||||
|
||||
```Gen
|
||||
modulator: TUN-N
|
||||
contained_by: N
|
||||
|
||||
tub_local:
|
||||
- SpikeTrainTraces (fullness: 50x, active: 0x, emptiness: 0x)
|
||||
# intricated with BEH-SOMA
|
||||
```
|
||||
|
||||
## IntegrateTunPossibility: Context
|
||||
|
||||
Qui controlliamo di essere lontani da uno spike train. Siamo in Day con BEH.
|
||||
|
||||
```Gen
|
||||
context: IntegrateTunPossibility
|
||||
|
||||
contained_by: TUN-N
|
||||
in_context: Fixed
|
||||
rf: 60x
|
||||
|
||||
condition: ( SpikeTrainTraces Empty ) # Day
|
||||
out_context: TunPossible
|
||||
```
|
||||
|
||||
## TUN-SYN: Modulator
|
||||
|
||||
Qui la PRE e la POST si predispongono per dare le condizioni a SYN di stabilire o eliminare una sinapsi. Per ora questo comportamento lo mettiamo in TUN perche’ non si tratta di creare o distruggere PRE o POST, ma di rendere disponibile a SYN la possibilita’ di creare o distruggere una SYN. Durante il Day c’e’ il TUN che mette a disposizione, durante il Night SYN crea o distrugge gli accoppiamenti PRE POST.
|
||||
|
||||
ATTENZIONE: Questo e POST e’ da cambiare, perche’ c’e’ il passaggio da TubPoss a TubPossSyn a TubAct. E’ la SYN che passa in TubAct.
|
||||
|
||||
> Minutes/hours Time Scale
|
||||
|
||||
```Gen
|
||||
modulator: TUN-SYN
|
||||
contained_by: TUN-N
|
||||
```
|
||||
|
||||
### TUN-SYN-AXO-PRE: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: TUN-SYN-AXO-PRE
|
||||
contained_by: TUN-SYN
|
||||
|
||||
modulates: BEH-AXO/expansion/BEH-PRE
|
||||
# qui stiamo modulando fullness e actual del tub BEH-PRE associandoli
|
||||
# a tub_modulation prePos e PreAct.
|
||||
|
||||
tub_modulation: # in TUN agiamo su fullness <-> active
|
||||
- fulMod ( fullness: None, active: BEH-PRE/fullness, empty: 0x ) # riferimento a possible di BEH-PRE
|
||||
- actMod ( fullness: None, active: BEH-PRE/active, empty: BEH-PRE/emptiness ) # riferimento a active di BEH-PRE
|
||||
|
||||
context_intricated:
|
||||
- TunPossible ( contained_by: TUN-N )
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
```Gen
|
||||
context: CheckTunSynAxoPrePossibility
|
||||
contained_by: TUN-SYN-AXO-PRE
|
||||
|
||||
in_context: TunPossible
|
||||
rf: ( active: 60x )
|
||||
|
||||
condition:
|
||||
out_context:
|
||||
```
|
||||
|
||||
#### Episode
|
||||
|
||||
```Gen
|
||||
episode: TunSynAxoPre
|
||||
contained_by: TUN-SYN-AXO-PRE
|
||||
|
||||
in_context: ??
|
||||
rf: 1x
|
||||
|
||||
hypothesis: NOT () AND NOT ()
|
||||
action: [ increase, decrease]
|
||||
trace: None
|
||||
```
|
||||
|
||||
### TUN-SYN-BD-POST: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: TUN-SYN-BD-POST
|
||||
|
||||
contained_by: TUN-SYN
|
||||
...
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
#### Episode
|
||||
|
||||
## TUN-CHAN: Modulator
|
||||
|
||||
Qui si modulano i canali ionici, sia quelli voltage (PRE/POST/SO/altro?) che quelli Neuro (POST/SO(inibitori)). Non si creano o si distruggono (lo si fa in Developing), ma si rendono attivi disattivi quelli presenti.
|
||||
|
||||
> Minutes/hours Time Scale
|
||||
|
||||
```Gen
|
||||
modulator: TUN-CHAN
|
||||
|
||||
contained_by: TUN-N
|
||||
```
|
||||
|
||||
### TUN-PRE-VGCC: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: TUN-PRE-VGCC
|
||||
|
||||
contained_by: TUN-CHAN
|
||||
|
||||
modulates: BEH-PRE/expansion/BEH-PRE-VCGG
|
||||
|
||||
tub_modulation: # in TUN agiamo su POS/ACT
|
||||
- posMod ( fullness: None, active: BEH-PRE-VCGG/fullness, empty: 0x) # riferimento a possible di BEH-PRE-VCGG
|
||||
- actMod ( fullness: None, active: BEH-PRE-VCGG/active, empty: BEH-PRE-VCGG/emptiness) # riferimento a active di BEH-PRE-VCGG
|
||||
# qui stiamo modulando possible e actual di BEH-PRE-VCGG associandoli
|
||||
# a posMod e actMod. Non serve associare una fullness perche'
|
||||
# la modulazione e' una pompa fra posMod e actMod e controlliamo
|
||||
# solo empty
|
||||
|
||||
context_intricated:
|
||||
- TunPossible ( contained_by: TUN-N )
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
```Gen
|
||||
context: Check
|
||||
contained_by: TUN-PRE-VGCC
|
||||
|
||||
in_context: TunPossible
|
||||
rf: ( active: 60x )
|
||||
|
||||
condition:
|
||||
out_context: TunPreVcgg
|
||||
```
|
||||
|
||||
#### Episode
|
||||
|
||||
```Gen
|
||||
episode: Tun
|
||||
contained_by: TUN-PRE-VGCC
|
||||
|
||||
in_context: TunPreVcgg
|
||||
rf: ( active: x )
|
||||
|
||||
hypothesis:
|
||||
action:
|
||||
trace:
|
||||
```
|
||||
|
||||
### TUN-POST-AMPA: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: TUN-POST-AMPA
|
||||
|
||||
contained_by: TUN-CHAN
|
||||
|
||||
modulates: BEH-POST/expansion/BEH-POST-IC
|
||||
|
||||
tub_modulation: # in TUN agiamo su POS/ACT
|
||||
- posMod ( fullness: None, active: BEH-POST-IC/fullness, empty: 0x) # riferimento a possible di BEH-PRE
|
||||
- actMod ( fullness: None, active: BEH-POST-IC/active, empty: BEH-POST-IC/emptiness) # riferimento a active di BEH-PRE
|
||||
|
||||
context_intricated:
|
||||
- TunPossible ( contained_by: TUN-N )
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
```Gen
|
||||
context: Check
|
||||
contained_by: TUN-POST-IC
|
||||
|
||||
in_context: TunPossible
|
||||
rf: ( active: 60x )
|
||||
|
||||
condition:
|
||||
out_context: TunPostIc
|
||||
```
|
||||
|
||||
#### Episode
|
||||
|
||||
```Gen
|
||||
episode: ?
|
||||
contained_by: TUN-POST-IC
|
||||
|
||||
in_context: TunPostIc
|
||||
rf: ( active: x )
|
||||
|
||||
hypothesis:
|
||||
action:
|
||||
trace:
|
||||
```
|
||||
|
||||
### TUN-SOMA-VCGG: Modulator
|
||||
|
||||
```Gen
|
||||
modulator: TUN-SOMA-VCGG
|
||||
|
||||
contained_by: TUN-CHAN
|
||||
|
||||
modulates: BEH-SOMA/expansion/BEH-SOMA-VCGG
|
||||
|
||||
expansion: BEH-SOMA-VCGG
|
||||
tub_modulation: # in TUN agiamo su POS/ACT
|
||||
- posMod ( fullness: None, active: BEH-SOMA-VCGG/fullness, empty: 0x) # riferimento a possible di BEH-PRE
|
||||
- actMod ( fullness: None, active: BEH-SOMA-VCGG/active, empty: BEH-SOMA-VCGG/emptiness) # riferimento a active di BEH-PRE
|
||||
|
||||
context_intricated:
|
||||
- TunPossible ( contained_by: TUN-N )
|
||||
|
||||
tub_local:
|
||||
|
||||
tub_intricated:
|
||||
```
|
||||
|
||||
#### Context
|
||||
|
||||
```Gen
|
||||
context: Check
|
||||
contained_by: TUN-SOMA-VCGG
|
||||
|
||||
in_context: TunPossible
|
||||
rf: ( active: 60x )
|
||||
|
||||
condition:
|
||||
out_context: TunSomaVcgg
|
||||
```
|
||||
|
||||
#### Episode
|
||||
|
||||
```Gen
|
||||
episode: ?
|
||||
contained_by: TUN-PRE-VGCC
|
||||
|
||||
in_context: TunSomaVcgg
|
||||
rf: ( active: x )
|
||||
|
||||
hypothesis:
|
||||
action:
|
||||
trace:
|
||||
```
|
||||
@@ -0,0 +1,87 @@
|
||||
Excellent question. The **timing and control** of retrograde signal release are precisely regulated and differ dramatically between these messengers, which is central to their distinct roles in plasticity. Here’s a detailed breakdown.
|
||||
|
||||
---
|
||||
|
||||
### **1. Nitric Oxide (NO) – The Fast, Activity-Gated Burst**
|
||||
|
||||
* **Time Scale of Release: Milliseconds to Seconds.**
|
||||
* **Key Influencing Factors:**
|
||||
* **NMDAR Activation & Ca²⁺ Influx:** The primary trigger. Strong postsynaptic depolarization relieves the Mg²⁺ block of NMDARs. Ca²⁺ influx through NMDARs binds to **calmodulin**.
|
||||
* **Calmodulin Binding to nNOS:** The Ca²⁺/calmodulin complex directly binds to and activates **neuronal Nitric Oxide Synthase (nNOS)**, which is often physically tethered to the NMDAR complex via PSD-95.
|
||||
* **Production & Diffusion:** NO is a **gasotransmitter**; it is synthesized *on-demand* and diffuses freely in all directions (~µm range) without vesicular release. Its production stops as soon as Ca²⁺ levels drop.
|
||||
* **Kinetics:**
|
||||
* **Onset:** Extremely fast (<100 ms after strong Ca²⁺ influx).
|
||||
* **Duration:** Brief pulse (seconds). NO is highly reactive and has a short half-life (~1-5 sec) due to scavenging by hemoglobin, superoxide, and other molecules.
|
||||
* **Spatial Spread:** Limited, acts as a **local volume signal** to nearby presynaptic terminals and astrocytes.
|
||||
* **Functional Implication:** NO acts as a **fast, correlational signal**. It broadcasts: "*Strong, synchronous activation is happening right now at this precise postsynaptic site.*" Its speed and locality make it ideal for rapid presynaptic potentiation during **early-phase LTP induction**.
|
||||
|
||||
---
|
||||
|
||||
### **2. Endocannabinoids (eCBs, e.g., 2-AG) – The Intermediate, Demand-Specific Signal**
|
||||
|
||||
* **Time Scale of Release: Hundreds of Milliseconds to Tens of Seconds.**
|
||||
* **Key Influencing Factors:**
|
||||
* **Two Primary Triggers:**
|
||||
1. **Post-Synaptic Ca²⁺ Rise:** Moderate to strong increases in dendritic Ca²⁺ (via VGCCs or NMDARs) activate **calcium-sensitive phospholipase C (PLC)**.
|
||||
2. **Metabotropic Receptor Activation:** Group I mGluR (mGluR1/5) activation strongly stimulates **PLCβ** via Gq proteins.
|
||||
* **Synthesis Pathway:** Both triggers converge on **PLC**, which cleaves membrane phospholipids to produce **diacylglycerol (DAG)**. **DAG lipase α (DAGLα)**, often localized postsynaptically, then converts DAG to **2-AG**.
|
||||
* **Release:** 2-AG is **lipophilic** and diffuses across the membrane immediately upon synthesis (**no vesicular release required**).
|
||||
* **Kinetics:**
|
||||
* **Onset:** Fast, but slower than NO (~300 ms - 1 sec).
|
||||
* **Duration:** Can be a brief pulse (for DSE/DSI) or a sustained release (seconds to minutes) during prolonged mGluR activation, as in some forms of LTD.
|
||||
* **Termination:** Rapid and precise by **presynaptic reuptake** and enzymatic degradation (mainly by **monoacylglycerol lipase, MAGL**).
|
||||
* **Functional Implication:** eCBs are **bidirectional modulators**. A brief, large Ca²⁺ spike may cause short-term depression (DSE). **Sustained, moderate mGluR activation** (e.g., during low-frequency stimulation) leads to prolonged 2-AG release, inducing **long-term presynaptic LTD**. The timing encodes the *nature* of the plasticity.
|
||||
|
||||
---
|
||||
|
||||
### **3. Brain-Derived Neurotrophic Factor (BDNF) – The Slow, Regulated Secretion of a Trophic Factor**
|
||||
|
||||
* **Time Scale of Release: Seconds to Minutes, with Biphasic Secretion.**
|
||||
* **Key Influencing Factors:**
|
||||
* **Activity Pattern:** Requires **strong, sustained, or patterned activity** (e.g., theta-burst stimulation). Not triggered by single spikes.
|
||||
* **Two Pools and Release Modes:**
|
||||
1. **Constitutive Secretion:** Slow, continuous baseline release from the **trans-Golgi network**.
|
||||
2. **Activity-Dependent Secretion:** The critical mode for plasticity. Involves two sub-pools:
|
||||
* **Pre-synthesized Pool (Fast):** Mature BDNF is stored in **dense-core vesicles (DCVs)** in dendrites and spines. Strong Ca²⁺ influx (via L-type VGCCs and NMDARs) triggers **Ca²⁺-induced exocytosis** of these DCVs within **seconds**.
|
||||
* **Newly Synthesized Pool (Slow):** The activity signal (Ca²⁺/CREB) also drives **transcription of the *Bdnf* gene** and **local dendritic translation** of BDNF mRNA. This provides a delayed (**minutes to hours**) but sustained supply for release.
|
||||
* **Regulation is Highly Complex:** Controlled at the level of:
|
||||
* **Transcription** (multiple activity-sensitive promoters).
|
||||
* **mRNA trafficking** to dendrites.
|
||||
* **Translation** (regulated by CaMKII, FMRP, microRNAs).
|
||||
* **Proteolytic cleavage** of proBDNF to mature BDNF.
|
||||
* **Kinetics:**
|
||||
* **Fast Release Onset:** 1-5 seconds after strong stimulation (from DCV pool).
|
||||
* **Sustained Release:** Continues for **many minutes** as newly synthesized BDNF is made available.
|
||||
* **Clearance:** Slow relative to NO/eCBs. BDNF is cleared by endocytosis (via TrkB/p75 receptors) and diffusion, acting over longer distances (tens of µm).
|
||||
* **Functional Implication:** BDNF is not a fast "fire-and-forget" signal. It is a **sustained trophic command** that bridges the gap between initial synaptic activation and long-term structural change. Its release signifies: "*This event was important and repeated; prepare for lasting remodeling.*"
|
||||
|
||||
---
|
||||
|
||||
### **Summary Table: Temporal Logic of Retrograde Signal Release**
|
||||
|
||||
| Signal | Primary Trigger | Release Mechanism | Onset | Duration | Spatial Range | Key Role in Plasticity |
|
||||
|:------------------------|:--------------------------------------------------|:----------------------------------------------|:-------------------------------------------------|:------------------------------|:---------------------------|:-------------------------------------------------------------------|
|
||||
| **Nitric Oxide (NO)** | Strong NMDAR Ca²⁺ influx | Gas diffusion on synthesis | **< 100 ms** | **Seconds** (brief pulse) | Local (µm) | **Fast correlational signal** for early-LTP coordination. |
|
||||
| **Endocannabinoids (2-AG)** | 1) Moderate Ca²⁺ rise<br />2) mGluR1/5 activation | Lipid diffusion on synthesis | **~300 ms - 1 sec** | **Seconds to minutes** (scalable) | Local to paracrine (µm) | **Bidirectional modulator.** Brief→STD; Sustained→LTD. |
|
||||
| **BDNF** | Strong/patterned firing (L-VGCC, NMDAR) | **Regulated exocytosis** from dense-core vesicles | **1-5 sec** (fast pool)<br />**Minutes** (new synthesis) | **Minutes to hours** (sustained) | Long-distance (tens of µm) | **Trophic command signal** for switch to late-LTP & structural change. |
|
||||
|
||||
---
|
||||
|
||||
### **Critical Integration: How These Signals Work as a Cascade**
|
||||
|
||||
The **sequence and coincidence** of these releases are crucial:
|
||||
|
||||
1. **Strong Tetanus:** Massive glutamate release → **NMDAR Ca²⁺ influx**.
|
||||
2. **Immediate (ms):** **NO** is produced, rapidly potentiating presynaptic release.
|
||||
3. **Early (100s ms - sec):** Ca²⁺ and mGluR activation may produce **eCBs**, but strong depolarization often suppresses eCB-LTD in favor of LTP.
|
||||
4. **Critical Window (sec - min):** Sustained Ca²⁺ activates CREB and triggers **BDNF exocytosis**. The released BDNF:
|
||||
* Acts **presynaptically** (via TrkB) to consolidate potentiation and initiate the switch to long-term changes.
|
||||
* Acts **postsynaptically** in an autocrine/paracrine manner to enhance its own synthesis and drive spine growth.
|
||||
|
||||
**In essence, the postsynapse uses a layered communication strategy:**
|
||||
|
||||
* **NO** is for **instantaneous coordination.**
|
||||
* **eCBs** are for **intermediate-term, reversible modulation.**
|
||||
* **BDNF** is for **long-term, structural commitment.**
|
||||
|
||||
The specific pattern of presynaptic activity and postsynaptic depolarization *selects* which retrograde signal cocktail is released, thereby determining both the **sign (potentiation/depression)** and **duration (short-term/long-term)** of the synaptic change.
|
||||
@@ -0,0 +1,486 @@
|
||||
# **Detailed Temporal Dynamics of Postsynaptic Response and Plasticity**
|
||||
|
||||
*From glutamate binding to structural consolidation, with concentration changes, receptor trafficking, and calcium signaling across timescales*
|
||||
|
||||
---
|
||||
|
||||
## **Baseline State (Resting Spine)**
|
||||
|
||||
**Time:** Continuous
|
||||
**Postsynaptic [Ca²⁺]:** ~50-100 nM
|
||||
**Membrane Potential (Vₘ):** -70 mV
|
||||
**AMPARs in PSD:** 10-20 receptors (GluA1/GluA2 heteromers)
|
||||
**NMDARs in PSD:** 5-10 receptors (GluN1/GluN2B)
|
||||
**Mg²⁺ block of NMDARs:** ~80% at -70 mV
|
||||
**CaMKII state:** Mostly inactive (α:β ≈ 3:1 ratio)
|
||||
**PSD-95 clusters:** ~300 molecules per PSD
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 1: FAST TIMESCALE (0-100 ms) - RECEPTOR ACTIVATION**
|
||||
|
||||
### **0.0-0.2 ms: Glutamate Arrival and Binding**
|
||||
|
||||
```
|
||||
Presynaptic glutamate release (~5000 molecules)
|
||||
↓
|
||||
Diffusion across 20 nm synaptic cleft (t ≈ 0.1 ms)
|
||||
↓
|
||||
**Glutamate concentration in cleft:**
|
||||
- Peak: 1-3 mM at PSD surface
|
||||
- Rapid clearance by EAATs (t½ ≈ 1 ms)
|
||||
↓
|
||||
**Simultaneous binding to:**
|
||||
1. **AMPARs (ionotropic, fast):**
|
||||
- 2 glutamate molecules bind per channel
|
||||
- Binding Kd ≈ 500 µM
|
||||
- Channel opens in ~0.2 ms
|
||||
|
||||
2. **NMDARs (ionotropic, slow):**
|
||||
- Requires glutamate + glycine/D-serine
|
||||
- Binding Kd ≈ 1-5 µM
|
||||
- Mg²⁺ block prevents opening at rest
|
||||
|
||||
3. **mGluRs (metabotropic):**
|
||||
- Group I mGluRs (mGluR1/5)
|
||||
- G-protein coupled, slower signaling
|
||||
```
|
||||
|
||||
### **0.2-2.0 ms: AMPAR-Mediated Depolarization**
|
||||
|
||||
```
|
||||
**For each open AMPAR:**
|
||||
- Conductance: 8-12 pS (single channel)
|
||||
- Reversal potential: 0 mV
|
||||
- **Na⁺ influx:** ~3000 ions/channel/ms
|
||||
- K⁺ efflux: ~1000 ions/channel/ms
|
||||
|
||||
**Net effect at spine head:**
|
||||
Without other inputs: EPSP amplitude = 0.5-2 mV
|
||||
With 20 AMPARs open: Current = 10-30 pA
|
||||
Depolarization to Vₘ ≈ -60 mV
|
||||
```
|
||||
|
||||
### **1.0-5.0 ms: NMDAR Activation (if depolarized)**
|
||||
|
||||
```
|
||||
**Requirement:** Vₘ > -40 mV to relieve Mg²⁺ block
|
||||
**Coincidence detection window:** 5-10 ms
|
||||
|
||||
If depolarized (from AMPARs or bAP):
|
||||
↓
|
||||
Mg²⁺ expelled from NMDAR channel
|
||||
↓
|
||||
**NMDAR opens with characteristic:**
|
||||
- Slow kinetics (τrise ≈ 10 ms, τdecay ≈ 50-100 ms)
|
||||
- High Ca²⁺ permeability (PCa/PNa ≈ 10:1)
|
||||
- **Single channel Ca²⁺ influx:** ~5000 Ca²⁺ ions/ms
|
||||
↓
|
||||
**Local [Ca²⁺] in spine head:**
|
||||
- Baseline: 100 nM
|
||||
- With NMDAR activation: **→ 1-10 µM**
|
||||
- With NMDAR + bAP coincidence: **→ 10-30 µM**
|
||||
```
|
||||
|
||||
### **5.0-50 ms: Calcium Dynamics and Clearance**
|
||||
|
||||
```
|
||||
**Calcium sources in spine:**
|
||||
1. NMDARs (main source for plasticity)
|
||||
2. Voltage-gated Ca²⁺ channels (VGCCs) from bAP
|
||||
3. Internal stores (IP₃R, RyR)
|
||||
|
||||
**Calcium buffers in spine:**
|
||||
- Calbindin-D28K (Kd ≈ 200 nM)
|
||||
- Parvalbumin (Kd ≈ 10 nM)
|
||||
- Calmodulin (Ca²⁺ sensor, Kd ≈ 1-10 µM)
|
||||
|
||||
**Clearance mechanisms:**
|
||||
1. Plasma Membrane Ca²⁺ ATPase (PMCA):
|
||||
- High affinity (Kd ≈ 100 nM)
|
||||
- Slow: clears ~30 Ca²⁺/sec per pump
|
||||
|
||||
2. Sodium-Calcium Exchanger (NCX):
|
||||
- Low affinity (Kd ≈ 1 µM)
|
||||
- Fast: 3 Na⁺ in, 1 Ca²⁺ out
|
||||
|
||||
3. SERCA pumps into ER:
|
||||
- If spine has smooth ER
|
||||
|
||||
4. Mitochondrial uptake (larger spines):
|
||||
- MCU (mitochondrial Ca²⁺ uniporter)
|
||||
- Kd ≈ 10-20 µM
|
||||
|
||||
**Result:**
|
||||
- 90% Ca²⁺ cleared in 50-100 ms
|
||||
- Returns to baseline [Ca²⁺] in 200-500 ms
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 2: MEDIUM TIMESCALE (100 ms - 10 sec) - SIGNALING CASCADES**
|
||||
|
||||
### **Calcium-Decoded Plasticity Decision**
|
||||
|
||||
```
|
||||
**The "Calcium Rule":**
|
||||
[Ca²⁺] amplitude × duration → plasticity direction
|
||||
|
||||
**Thresholds:**
|
||||
- LTD: 1-5 µM sustained (100 ms - 1 sec)
|
||||
- LTP: >10 µM brief (10-50 ms)
|
||||
- LTP requires **rapid rise** (d[Ca²⁺]/dt > 0.5 µM/ms)
|
||||
```
|
||||
|
||||
### **LTD Pathway (Moderate Ca²⁺)**
|
||||
|
||||
```
|
||||
[Ca²⁺] = 1-5 µM for >100 ms
|
||||
↓
|
||||
Calcium binds Calmodulin (CaM)
|
||||
↓
|
||||
**Activates Calcineurin (CaN, PP2B):**
|
||||
- Phosphatase, Kd ≈ 0.5 µM Ca²⁺
|
||||
- Activated at lower [Ca²⁺] than CaMKII
|
||||
↓
|
||||
CaN dephosphorylates Inhibitor-1
|
||||
↓
|
||||
**Releases inhibition of Protein Phosphatase-1 (PP1)**
|
||||
↓
|
||||
PP1 dephosphorylates:
|
||||
1. GluA1 at S845 → increases endocytosis
|
||||
2. Stargazin → reduces AMPAR synaptic retention
|
||||
3. Other targets promoting AMPAR removal
|
||||
↓
|
||||
**Result: AMPAR internalization begins in 30-60 sec**
|
||||
```
|
||||
|
||||
### **LTP Pathway (High Ca²⁺)**
|
||||
|
||||
```
|
||||
[Ca²⁺] > 10 µM with rapid rise
|
||||
↓
|
||||
Calcium binds Calmodulin (CaM)
|
||||
↓
|
||||
**Activates Ca²⁺/Calmodulin Kinase II (CaMKII):**
|
||||
- 12-subunit holoenzyme
|
||||
- Each subunit has autoinhibitory domain
|
||||
- Requires Ca²⁺/CaM binding to activate
|
||||
↓
|
||||
**Autophosphorylation at T286:**
|
||||
- First subunit phosphorylates neighbor
|
||||
- Creates Ca²⁺-independent activity
|
||||
- **Molecular switch:** stays active after Ca²⁺ clears
|
||||
↓
|
||||
**Active CaMKII translocates to PSD:**
|
||||
- Binds to NR2B subunit of NMDAR
|
||||
- Binds to α-actinin (actin linker)
|
||||
- Becomes structural component of PSD
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 3: SLOW TIMESCALE (10 sec - 10 min) - RECEPTOR TRAFFICKING**
|
||||
|
||||
### **LTD Execution (1-10 minutes)**
|
||||
|
||||
```
|
||||
**Clathrin-mediated endocytosis:**
|
||||
PP1 activity → GluA1 S845 dephosphorylated
|
||||
↓
|
||||
Increased binding to AP2 adaptor complex
|
||||
↓
|
||||
**Clathrin coats form at spine periphery (t ≈ 1-2 min)**
|
||||
↓
|
||||
AMPARs internalized via endocytosis
|
||||
↓
|
||||
**Vesicles transported to early endosomes**
|
||||
↓
|
||||
Receptors either:
|
||||
1. Recycled back to surface (silent synapses)
|
||||
2. Degraded in lysosomes (long-term LTD)
|
||||
↓
|
||||
**By 10 min:**
|
||||
- 30-50% reduction in surface AMPARs
|
||||
- EPSP amplitude decreases proportionally
|
||||
```
|
||||
|
||||
### **LTP Execution (1-10 minutes)**
|
||||
|
||||
```
|
||||
**Rapid AMPAR insertion:**
|
||||
CaMKII phosphorylates:
|
||||
1. **Stargazin (TARP γ-2) at S9:**
|
||||
- Increases binding to PSD-95
|
||||
- **Traps AMPARs in PSD** (Kd improves 10×)
|
||||
|
||||
2. **SynGAP (RasGAP):**
|
||||
- Phosphorylation inhibits Ras inactivation
|
||||
- Increases ERK/MAPK signaling
|
||||
↓
|
||||
**Exocytosis of AMPARs:**
|
||||
1. From recycling endosomes (Rab11-dependent)
|
||||
2. From intracellular pools
|
||||
3. **Insertion at extrasynaptic sites first**
|
||||
↓
|
||||
**Lateral diffusion into PSD:**
|
||||
- AMPARs diffuse in membrane (D ≈ 0.1 µm²/s)
|
||||
- Phosphorylated Stargazin binds PSD-95
|
||||
- **Trapped in PSD for minutes-hours**
|
||||
↓
|
||||
**By 10 min:**
|
||||
- 50-100% increase in surface AMPARs
|
||||
- EPSP amplitude increases 50-200%
|
||||
```
|
||||
|
||||
### **Phosphorylation State Changes**
|
||||
|
||||
```
|
||||
**AMPAR modifications during LTP:**
|
||||
- **GluA1 S831:** Phosphorylated by CaMKII/PKC
|
||||
→ Increases single channel conductance (γ from 8→12 pS)
|
||||
|
||||
- **GluA1 S845:** Phosphorylated by PKA
|
||||
→ Increases open probability (Po from 0.8→0.95)
|
||||
|
||||
- **GluA2 S880:** Phosphorylated by PKC
|
||||
→ Regulates binding to GRIP/ABP vs PICK1
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 4: METABOLIC SUPPORT (10 min - 2 hours) - PROTEIN SYNTHESIS**
|
||||
|
||||
### **Local Translation in Spine**
|
||||
|
||||
```
|
||||
**Trigger:**
|
||||
1. CaMKII activation
|
||||
2. mGluR activation
|
||||
3. BDNF-TrkB signaling
|
||||
|
||||
**Pathways:**
|
||||
1. **mTOR pathway:**
|
||||
- PI3K → Akt → mTORC1
|
||||
- Phosphorylates 4E-BP, releases eIF4E
|
||||
- **Initiates cap-dependent translation**
|
||||
|
||||
2. **MAPK pathway:**
|
||||
- Ras → Raf → MEK → ERK
|
||||
- Phosphorylates translation factors
|
||||
↓
|
||||
**Dendritic mRNA translation begins (t ≈ 20-30 min):**
|
||||
Key mRNAs locally translated:
|
||||
1. **CaMKIIα** - more kinase molecules
|
||||
2. **GluA1** - new AMPAR subunits
|
||||
3. **Arc/Arg3.1** - regulates AMPAR trafficking
|
||||
4. **PSD-95** - scaffolding protein
|
||||
5. **Homer1a** - regulates mGluR signaling
|
||||
↓
|
||||
**New proteins synthesized locally:**
|
||||
- Concentration increases over 1-2 hours
|
||||
- Replaces initial plasticity with stable changes
|
||||
```
|
||||
|
||||
### **Retrograde Signaling Synthesis**
|
||||
|
||||
```
|
||||
**For LTP:**
|
||||
Ca²⁺ → activates nNOS (neuronal nitric oxide synthase)
|
||||
↓
|
||||
**NO synthesis from arginine:**
|
||||
- Diffusion constant: ~3300 µm²/s
|
||||
- Half-life: ~1-5 seconds
|
||||
- Diffuses 10-20 µm to presynaptic terminal
|
||||
↓
|
||||
**BDNF synthesis and release:**
|
||||
- Transcription begins in 30 min
|
||||
- Release occurs 1-2 hours post-induction
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 5: STRUCTURAL CONSOLIDATION (2 hours - 24 hours)**
|
||||
|
||||
### **Actin Cytoskeleton Remodeling**
|
||||
|
||||
```
|
||||
**Spine enlargement (LTP):**
|
||||
Active CaMKII → phosphorylates **Profilin**
|
||||
↓
|
||||
Profilin binds actin monomers → promotes polymerization
|
||||
↓
|
||||
**Rho GTPase activation:**
|
||||
- Rac1 activated → promotes actin branching (via Arp2/3)
|
||||
- Cdc42 activated → promotes filopodia formation
|
||||
↓
|
||||
**Actin polymerization in spine head:**
|
||||
- F-actin increases 2-3×
|
||||
- Spine volume increases over 1-3 hours
|
||||
↓
|
||||
**PSD expansion:**
|
||||
- More space for AMPARs
|
||||
- More PSD-95 scaffolding
|
||||
↓
|
||||
**By 6 hours:** Spine volume increased 50-100%
|
||||
```
|
||||
|
||||
### **Nuclear Signaling and Gene Expression**
|
||||
|
||||
```
|
||||
**Signals reach nucleus (1-3 hours):**
|
||||
1. **CaMKIV translocation:**
|
||||
- Activated by Ca²⁺ in dendrites
|
||||
- Translocates to nucleus when phosphorylated
|
||||
|
||||
2. **MAPK/ERK translocation:**
|
||||
- Activated at synapse
|
||||
- Travels to nucleus (active transport)
|
||||
|
||||
3. **CREB phosphorylation:**
|
||||
- At S133 by CaMKIV/PKA/RSK
|
||||
- Recruits CBP/p300 coactivators
|
||||
↓
|
||||
**Transcriptional activation (3-6 hours):**
|
||||
Early genes (IEGs):
|
||||
- c-Fos, c-Jun, Egr1/Zif268
|
||||
|
||||
Late genes (plasticity-related):
|
||||
- **BDNF** (brain-derived neurotrophic factor)
|
||||
- **GluA1** (AMPAR subunit)
|
||||
- **CaMKIIα**
|
||||
- **Arc**
|
||||
- **Homer1a**
|
||||
↓
|
||||
**New proteins synthesized in soma (6-12 hours)**
|
||||
↓
|
||||
**Transport to dendrites (12-24 hours)**
|
||||
↓
|
||||
**Incorporation into spine (24+ hours)**
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 6: VERY SLOW TIMESCALE (Days - Weeks) - STRUCTURAL STABILITY**
|
||||
|
||||
### **Spine Maturation and Stabilization**
|
||||
|
||||
```
|
||||
**Day 1-7:**
|
||||
- **PSD thickening:** from 30 nm → 50 nm
|
||||
- **AMPAR subtype switch:**
|
||||
GluA2-lacking (Ca²⁺-permeable) → GluA2-containing
|
||||
(Occurs over days via subunit replacement)
|
||||
|
||||
- **Synaptic adhesion molecules:**
|
||||
Neuroligin-Neurexin complexes stabilize contact
|
||||
|
||||
**Week 1-4:**
|
||||
- **Spine shape changes:**
|
||||
Thin → Mushroom (LTP)
|
||||
Mushroom → Thin (LTD)
|
||||
|
||||
- **Presynaptic coordination:**
|
||||
Active zone aligns with expanded PSD
|
||||
|
||||
- **Perisynaptic astrocyte processes:**
|
||||
Enwrap mature synapse for metabolic support
|
||||
```
|
||||
|
||||
### **Homeostatic Scaling**
|
||||
|
||||
```
|
||||
**Days 2-7:**
|
||||
If overall neuron firing rate changes significantly:
|
||||
↓
|
||||
**Global scaling mechanisms:**
|
||||
1. **TNFα signaling:** from astrocytes
|
||||
2. **BDNF level changes**
|
||||
↓
|
||||
All synapses on neuron scaled up or down
|
||||
↓
|
||||
**AMPAR number adjusted** while relative differences maintained
|
||||
↓
|
||||
**Preserves signal-to-noise ratio** of individual synapses
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **COMPLETE LTP TIMELINE EXAMPLE**
|
||||
|
||||
### **Induction (Seconds)**
|
||||
|
||||
```
|
||||
T=0 ms: Presynaptic glutamate release
|
||||
T=10 ms: bAP arrives at spine (coincidence)
|
||||
T=15 ms: [Ca²⁺] peaks at 25 µM
|
||||
T=50 ms: Ca²⁺ clears to 1 µM
|
||||
T=1 sec: CaMKII autophosphorylated (T286)
|
||||
T=10 sec: CaMKII translocates to PSD
|
||||
```
|
||||
|
||||
### **Early Expression (Minutes)**
|
||||
|
||||
```
|
||||
T=1 min: AMPARs inserted (from recycling endosomes)
|
||||
T=2 min: EPSP amplitude increases 100%
|
||||
T=5 min: Stargazin phosphorylated, AMPARs trapped
|
||||
T=10 min: Early LTP established
|
||||
```
|
||||
|
||||
### **Protein Synthesis-Dependent Phase (Hours)**
|
||||
|
||||
```
|
||||
T=30 min: Local translation begins (CaMKIIα, GluA1)
|
||||
T=1 hour: BDNF transcription initiated
|
||||
T=2 hours: Spine volume begins increasing
|
||||
T=3 hours: New proteins from local synthesis incorporated
|
||||
T=6 hours: Spine volume increased 60%
|
||||
```
|
||||
|
||||
### **Late Maintenance (Days)**
|
||||
|
||||
```
|
||||
T=12 hours: New proteins from soma arrive
|
||||
T=24 hours: Structural changes stabilized
|
||||
T=48 hours: GluA2 subunits replace GluA1 homomers
|
||||
T=7 days: Mature mushroom spine established
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **CALCIUM SIGNALING THRESHOLDS SUMMARY**
|
||||
|
||||
| \[Ca²⁺\] Range | Duration | Sensor | Outcome |
|
||||
|----------------|----------------|-------------|----------------------------|
|
||||
| < 0.5 µM | Any | None | Baseline signaling |
|
||||
| 0.5-1 µM | \>1 sec | Calcineurin | Weak LTD |
|
||||
| 1-5 µM | 100 ms-1 sec | Calcineurin | Strong LTD |
|
||||
| 5-10 µM | Brief (<50 ms) | CaMKII | Weak LTP |
|
||||
| \>10 µM | Brief (<50 ms) | CaMKII | Strong LTP |
|
||||
| \>20 µM | Any | Calpain | Pathological, spine damage |
|
||||
|
||||
---
|
||||
|
||||
## **KEY BIOLOGICAL PRINCIPLES**
|
||||
|
||||
1. **Spine as Biochemical Compartment:**
|
||||
- Neck resistance (50-500 MΩ) restricts diffusion
|
||||
- Allows independent [Ca²⁺] signaling in each spine
|
||||
- Enables synapse-specific plasticity
|
||||
2. **Kinetic Competition:**
|
||||
- Calcineurin activates faster at low [Ca²⁺] (Kd ≈ 0.5 µM)
|
||||
- CaMKII requires higher [Ca²⁺] but has positive feedback
|
||||
- Winner-takes-all decision based on [Ca²⁺] time course
|
||||
3. **Energy Requirements:**
|
||||
- Each AMPAR insertion: ~1000 ATP
|
||||
- CaMKII autophosphorylation: 1 ATP/subunit
|
||||
- Protein synthesis: ~4 ATP/amino acid
|
||||
- ATP supplied by astrocyte lactate
|
||||
4. **Timescale Coupling:**
|
||||
- Fast (ms): Receptor activation
|
||||
- Medium (min): Trafficking existing proteins
|
||||
- Slow (hours): Making new proteins
|
||||
- Very slow (days): Structural changes
|
||||
|
||||
This postsynaptic timeline shows how a brief glutamate signal triggers a cascade of events across multiple timescales, converting transient electrical activity into lasting structural and functional changes that underlie learning and memory.
|
||||
@@ -0,0 +1,708 @@
|
||||
# **Detailed Temporal Dynamics of Presynaptic Neurotransmitter Release**
|
||||
|
||||
*With concentration changes, calcium clearance mechanisms, and multi-timescale modifications of release probability (Pr)*
|
||||
|
||||
---
|
||||
|
||||
## **Baseline State (Resting Condition)**
|
||||
|
||||
**Time:** Continuous resting state
|
||||
**Presynaptic [Ca²⁺]:** ~100 nM (resting cytosolic concentration)
|
||||
**Pr baseline:** 0.3 (30% release probability per action potential)
|
||||
**Ready vesicles:** 5-10 vesicles in readily releasable pool (RRP)
|
||||
**ATP/GTP levels:** Normal
|
||||
**Phosphorylation state:** Baseline kinase/phosphatase balance
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 1: FAST TIMESCALE (0-100 ms) - SINGLE SPIKE CYCLE**
|
||||
|
||||
### **0.0-0.5 ms: Action Potential Arrival & Calcium Influx**
|
||||
|
||||
```
|
||||
AP depolarization (+30mV) reaches terminal
|
||||
↓
|
||||
VGCCs (P/Q-type) open with ~50% probability
|
||||
↓
|
||||
Ca²⁺ enters through ~20 channels per active zone
|
||||
↓
|
||||
**Local [Ca²⁺] at release site: 100 nM → 10-50 µM** (peak in nanodomain)
|
||||
↓
|
||||
Calcium diffuses ~20-30 nm to docked vesicles
|
||||
↓
|
||||
**PROBABILISTIC DECISION POINT:**
|
||||
Time window for decision: ~0.2-0.5 ms
|
||||
```
|
||||
|
||||
### **0.5-2.0 ms: Release Decision & Execution**
|
||||
|
||||
```
|
||||
├── **PATH A: RELEASE OCCURS (Pr = 0.3)**
|
||||
│ ↓
|
||||
│ [Ca²⁺] at Synaptotagmin > 10 µM
|
||||
│ ↓
|
||||
│ 3-5 Ca²⁺ ions bind to C2 domains of Synaptotagmin-1
|
||||
│ ↓
|
||||
│ Synaptotagmin inserts into membrane (Kd ~5-10 µM)
|
||||
│ ↓
|
||||
│ **SNARE complex completes zippering** (t ≈ 0.8 ms)
|
||||
│ ↓
|
||||
│ Fusion pore opens (diameter ~1 nm initially)
|
||||
│ ↓
|
||||
│ **~5000 glutamate molecules released** (t = 1-2 ms)
|
||||
│ ↓
|
||||
│ Fusion pore expands → full fusion
|
||||
│ ↓
|
||||
│ Vesicle membrane incorporated into plasma membrane
|
||||
│
|
||||
└── **PATH B: NO RELEASE (1-Pr = 0.7)**
|
||||
↓
|
||||
[Ca²⁺] at Synaptotagmin < 5 µM (insufficient binding)
|
||||
↓
|
||||
Calcium buffers (calbindin, parvalbumin) bind Ca²⁺
|
||||
↓
|
||||
Vesicle remains docked/primed
|
||||
↓
|
||||
No fusion → **silent spike**
|
||||
```
|
||||
|
||||
### **2.0-50 ms: Calcium Clearance & Fast Recovery**
|
||||
|
||||
```
|
||||
**Primary clearance mechanisms:**
|
||||
1. Plasma Membrane Ca²⁺ ATPase (PMCA):
|
||||
- Kd ~100-200 nM
|
||||
- Rate: 30 Ca²⁺/sec per pump
|
||||
- **Clears 90% of Ca²⁺ in 10-20 ms**
|
||||
|
||||
2. Na⁺/Ca²⁺ exchanger (NCX):
|
||||
- Lower affinity (Kd ~1 µM) but higher capacity
|
||||
- Important for bulk clearance
|
||||
|
||||
3. Mitochondrial uptake:
|
||||
- MCU (mitochondrial Ca²⁺ uniporter)
|
||||
- Kd ~10-20 µM
|
||||
- Slower but provides long-term buffering
|
||||
|
||||
4. Endoplasmic reticulum uptake (SERCA):
|
||||
- Sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase
|
||||
- Kd ~0.5 µM
|
||||
|
||||
**Result:** [Ca²⁺] returns to ~500 nM by 50 ms
|
||||
**Residual [Ca²⁺]:** ~200-300 nM persists for 100-500 ms
|
||||
**Vesicle retrieval:** Clathrin-mediated endocytosis begins at ~1 sec
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 2: SHORT-TERM PLASTICITY (100 ms - 10 sec)**
|
||||
|
||||
### **Example: Spike Train at 50 Hz (20 ms interval)**
|
||||
|
||||
```
|
||||
Spike 1: Pr = 0.3 → Release probability
|
||||
Spike 2 (20 ms later):
|
||||
Residual [Ca²⁺] = 300 nM
|
||||
Pr increases to 0.45 (facilitation)
|
||||
Ca²⁺ influx adds to residual Ca²⁺
|
||||
|
||||
Spike 3 (40 ms):
|
||||
Residual [Ca²⁺] accumulates to 400 nM
|
||||
Pr = 0.55
|
||||
But RRP depletion begins (STD component)
|
||||
|
||||
Spike 4 (60 ms):
|
||||
RRP depleted to 60%
|
||||
Effective Pr = 0.5 × 0.6 = 0.3 (balance facilitation/depletion)
|
||||
|
||||
Spike 5-10:
|
||||
Steady-state: Pr ~0.25, RRP ~40% of baseline
|
||||
```
|
||||
|
||||
### **Molecular Mechanisms of Short-Term Changes:**
|
||||
|
||||
```
|
||||
**Facilitation (0-500 ms):**
|
||||
Residual Ca²⁺ (~200-500 nM) → binds to Calmodulin
|
||||
↓
|
||||
Ca²⁺-Calmodulin binds to Munc13
|
||||
↓
|
||||
Munc13 increases priming rate 3-5×
|
||||
↓
|
||||
**Pr increases for next spike**
|
||||
|
||||
**Depression (0-2 sec):**
|
||||
Vesicle fusion → RRP depletion
|
||||
↓
|
||||
Recovery requires:
|
||||
1. Vesicle recycling (endocytosis: 1-10 sec)
|
||||
2. Vesicle repriming (2-30 sec)
|
||||
3. Reserve pool mobilization (seconds)
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 3: MEDIUM-TERM ADAPTATION (10 sec - 10 min)**
|
||||
|
||||
### **Example: LTP Induction at 100 Hz for 1 sec (Tetanus)**
|
||||
|
||||
```
|
||||
**0-1 sec: High-frequency stimulation**
|
||||
- 100 APs delivered
|
||||
- Massive Ca²⁺ accumulation in terminal
|
||||
- [Ca²⁺] builds to sustained 1-2 µM
|
||||
- Complete RRP depletion
|
||||
- Strong glutamate release
|
||||
|
||||
**1-30 sec: Retrograde signaling arrives**
|
||||
Postsynaptic spine produces:
|
||||
1. Nitric Oxide (NO) - diffuses in seconds
|
||||
2. Brain-Derived Neurotrophic Factor (BDNF) - released in minutes
|
||||
3. Endocannabinoids (eCBs) - for LTD case
|
||||
|
||||
NO diffuses into presynaptic terminal (t ≈ 5-10 sec)
|
||||
↓
|
||||
**NO activates soluble guanylyl cyclase (sGC)**
|
||||
↓
|
||||
sGC produces cGMP from GTP
|
||||
↓
|
||||
**cGMP increases from ~1 nM to 100 nM**
|
||||
↓
|
||||
cGMP activates Protein Kinase G (PKG)
|
||||
```
|
||||
|
||||
### **30 sec - 5 min: PKG-Mediated Pr Enhancement**
|
||||
|
||||
```
|
||||
PKG phosphorylates multiple targets:
|
||||
|
||||
1. **VGCCs (P/Q-type):**
|
||||
- Phosphorylation at specific serine residues
|
||||
- Open probability increases from 0.5 → 0.7
|
||||
- More Ca²⁺ enters per AP
|
||||
|
||||
2. **Munc18:**
|
||||
- Enhanced interaction with Syntaxin
|
||||
- Vesicle priming rate increases 2×
|
||||
|
||||
3. **Synaptotagmin-1:**
|
||||
- Increased Ca²⁺ sensitivity (Kd decreases from 10→5 µM)
|
||||
- Faster binding kinetics
|
||||
|
||||
4. **RIM proteins:**
|
||||
- Enhanced vesicle tethering
|
||||
- Better VGCC-vesicle coupling
|
||||
|
||||
**Net effect by 5 min:**
|
||||
- Pr increases from 0.3 → 0.5
|
||||
- Baseline Ca²⁺ sensitivity increased
|
||||
- Readily Releasable Pool size increases 30%
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 4: SLOW CONSOLIDATION (10 min - 2 hours)**
|
||||
|
||||
### **Local Protein Synthesis (Presynaptic)**
|
||||
|
||||
```
|
||||
**30 min - 2 hours:**
|
||||
BDNF binds to TrkB receptors on presynaptic terminal
|
||||
↓
|
||||
Activation of PI3K/mTOR pathway
|
||||
↓
|
||||
**Local translation of presynaptic mRNAs:**
|
||||
1. VGCC subunits (α1A, β4)
|
||||
2. Synaptotagmin-1
|
||||
3. Munc13-1
|
||||
4. SNARE proteins
|
||||
|
||||
**Result by 2 hours:**
|
||||
- 50% more VGCCs clustered at active zone
|
||||
- 40% more Synaptotagmin molecules per vesicle
|
||||
- Pr stabilizes at 0.6
|
||||
```
|
||||
|
||||
### **Metabolic Support System**
|
||||
|
||||
```
|
||||
**Astrocyte coordination:**
|
||||
1. Glutamate uptake → converted to glutamine
|
||||
2. Glutamine exported to presynaptic terminal
|
||||
3. Presynaptic mitochondria increase oxidative phosphorylation
|
||||
4. ATP production increases 2× to support enhanced release
|
||||
|
||||
**Energy requirements:**
|
||||
- Vesicle recycling: ~10,000 ATP/vesicle
|
||||
- Ca²⁺ clearance: ~1 ATP/2 Ca²⁺ ions
|
||||
- Protein synthesis: ~4 ATP/amino acid
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **PHASE 5: STRUCTURAL CONSOLIDATION (2 hours - 24 hours)**
|
||||
|
||||
### **Nuclear Signaling & Gene Expression**
|
||||
|
||||
```
|
||||
**2-6 hours:**
|
||||
Persistent kinase activity (PKG, PKA, MAPK)
|
||||
↓
|
||||
CREB phosphorylation in presynaptic nucleus
|
||||
↓
|
||||
**Gene expression changes:**
|
||||
1. Structural proteins (Bassoon, Piccolo)
|
||||
2. Active zone components
|
||||
3. Vesicle cycle proteins
|
||||
4. Metabolic enzymes
|
||||
|
||||
**12-24 hours:**
|
||||
New proteins arrive via axonal transport
|
||||
↓
|
||||
**Active zone remodeling:**
|
||||
- Active zone area increases 30-50%
|
||||
- More docked vesicles (RRP size doubles)
|
||||
- VGCC-vesicle distance decreases to 15 nm
|
||||
- **Pr stabilizes at 0.7-0.8**
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **CALCIUM HOMEOSTASIS TIMELINE SUMMARY**
|
||||
|
||||
| Time | \[Ca²⁺\] at Release Site | Clearance Mechanism | Residual Effect |
|
||||
|--------|--------------------------|--------------------------|----------------------------|
|
||||
| 0 ms | 100 nM (baseline) | \- | \- |
|
||||
| 0.5 ms | 10-50 µM (peak) | Diffusion only | Fusion decision |
|
||||
| 5 ms | 1-5 µM | Fast buffers (calbindin) | Ca²⁺-calmodulin activation |
|
||||
| 20 ms | 500 nM | PMCA pumps active | Facilitation of next spike |
|
||||
| 100 ms | 300 nM | NCX contributes | Augmentation phase |
|
||||
| 1 sec | 200 nM | Mitochondrial uptake | Potentiation |
|
||||
| 10 sec | 150 nM | Steady-state clearance | LTP induction possible |
|
||||
| 1 min | 120 nM | Full homeostasis | \- |
|
||||
| 1 hour | 100 nM | Normal resting state | \- |
|
||||
|
||||
---
|
||||
|
||||
## **EXAMPLE: COMPLETE LTP TIMELINE**
|
||||
|
||||
### **Day 1: Induction Phase**
|
||||
|
||||
```
|
||||
**T=0:** 100 Hz tetanus (1 sec)
|
||||
**T=5 sec:** NO arrives at presynaptic terminal
|
||||
**T=30 sec:** cGMP peaks, PKG activated
|
||||
**T=5 min:** Pr increases to 0.45 (phosphorylation)
|
||||
**T=30 min:** Local protein synthesis begins
|
||||
**T=2 hours:** Pr = 0.55, structural proteins arriving
|
||||
**T=6 hours:** Active zone remodeling begins
|
||||
**T=24 hours:** Pr stabilizes at 0.65, active zone enlarged 40%
|
||||
```
|
||||
|
||||
### **Day 2-7: Maintenance**
|
||||
|
||||
```
|
||||
**Metabolic support ongoing:**
|
||||
- Astrocyte supplies glutamine/lactate
|
||||
- Mitochondrial density increases near active zone
|
||||
- Vesicle recycling efficiency improves
|
||||
|
||||
**Structural stabilization:**
|
||||
- New active zone material incorporated
|
||||
- Cytoskeleton reorganizes
|
||||
- Pr maintains at 0.65-0.70
|
||||
```
|
||||
|
||||
---
|
||||
|
||||
## **KEY BIOLOGICAL INSIGHTS**
|
||||
|
||||
1. **Pr is multi-dimensional:**
|
||||
- **Fast component:** Vesicle availability × Ca²⁺ sensitivity
|
||||
- **Slow component:** Protein composition × active zone geometry
|
||||
2. **Energy dependence:**
|
||||
- Ca²⁺ clearance requires constant ATP
|
||||
- Without ATP, [Ca²⁺] remains elevated → toxicity
|
||||
- Metabolic veto: Low ATP → release inhibition despite Ca²⁺
|
||||
3. **Timescale hierarchy:**
|
||||
- **ms:** Existing protein modification (phosphorylation)
|
||||
- **min:** Local protein synthesis
|
||||
- **hours:** Nuclear transcription
|
||||
- **days:** Structural reorganization
|
||||
4. **Homeostatic balance:**
|
||||
- Enhanced Pr increases metabolic demand
|
||||
- Requires coordinated astrocyte support
|
||||
- Long-term maintenance depends on energy availability
|
||||
|
||||
This detailed timeline shows how a single probabilistic event (vesicle release) is embedded in a complex, multi-timescale regulatory system that balances immediate communication needs with long-term information storage and metabolic sustainability.
|
||||
|
||||
---
|
||||
|
||||
---
|
||||
|
||||
---
|
||||
|
||||
Based on the provided document, here is a specification of the Short-Term Plasticity (STP/STD) and Long-Term Plasticity (LTP/LTD) mechanisms between the Presynapse and Postsynapse, detailing both internal processes and their interactions, with explicit timescales.
|
||||
|
||||
### **Summary: Primary Plasticity Mechanisms & Timescales**
|
||||
|
||||
| Mechanism | Primary Locus | Key Internal Trigger | Key Interactive Signal | Timescale | Functional Role |
|
||||
|-----------------------------------|------------------|-----------------------------------------------|-------------------------------------------------|------------------------------------|------------------------------------------------------------|
|
||||
| **Short-Term Depression (STD)** | **Presynaptic** | Vesicle pool depletion | Reduced glutamate release | **Fast (<100ms)** | Filters high-frequency bursts; transient synaptic fatigue. |
|
||||
| **Short-Term Potentiation (STP)** | **Presynaptic** | Residual Ca²⁺ buildup | Increased glutamate release probability ($P_r$) | **Fast to Medium (<100ms to 10s)** | Facilitates temporal summation; augments recent activity. |
|
||||
| **Long-Term Depression (LTD)** | **Postsynaptic** | Moderate, sustained Ca²⁺ influx (~1-5 µM) | Retrograde endocannabinoids (eCBs) | **Slow (Seconds to Minutes)** | Weakens ineffective connections; homeostatic adjustment. |
|
||||
| **Long-Term Potentiation (LTP)** | **Postsynaptic** | Strong, coincident Ca²⁺ influx (>10 µM) | Retrograde NO/BDNF | **Slow (Seconds to Minutes)** | Strengthens correlated pre- and postsynaptic activity. |
|
||||
| **Structural LTP/LTD** | **Both** | Persistent molecular tags & protein synthesis | Trophic factors & homeostatic scaling | **Structural (Days+)** | Embeds memory persistently via physical changes. |
|
||||
|
||||
---
|
||||
|
||||
### **Detailed Breakdown by Timescale**
|
||||
|
||||
#### **1. Fast Timescale (<100 ms): STP & STD Internal Mechanisms**
|
||||
|
||||
* **Presynaptic Internal (STD):** Rapid vesicle fusion and release depletes the readily releasable pool. This is a **presynaptic, internal** mechanism causing a transient decrease in synaptic strength.
|
||||
* **Presynaptic Internal (STP):** Residual Ca²⁺ from a preceding action potential lingers, increasing the release probability ($P_r$) for the next spike. This is a **presynaptic, internal** facilitatory mechanism.
|
||||
* **Interaction (Fast Signaling):** The presynapse releases **glutamate** (outgoing signal). The postsynapse receives it and, if sufficiently depolarized, opens NMDA receptors, allowing a **Ca²⁺ influx**. This **Ca²⁺ transient** is the **postsynaptic, internal** coincidence detector signal that initiates the cascade for slower plasticity.
|
||||
|
||||
#### **2. Medium Timescale (100 ms – 10 s): Augmentation & Modulation**
|
||||
|
||||
* **Presynaptic Internal:** Augmentation via Munc13 proteins modifies $P_r$ based on Ca²⁺ sensing. This is a **presynaptic, internal** continuation of STP.
|
||||
* **Postsynaptic Internal:** Metabotropic glutamate receptor (mGluR) activation modulates local spine excitability and prepares plasticity pathways. This is a **postsynaptic, internal** modulatory state.
|
||||
* **Interaction:** Largely an extension of fast signaling, setting the stage for slower decisions. The **pattern of glutamate release** interacts with the **postsynaptic voltage state**.
|
||||
|
||||
#### **3. Slow Timescale (Seconds – Minutes): LTP & LTD Decision & Expression**
|
||||
|
||||
This is the critical window for **bidirectional interaction** that establishes long-term change.
|
||||
|
||||
* **Postsynaptic Internal (The Decision):**
|
||||
* **LTP Trigger:** **High, localized Ca²⁺** (from strong NMDA activation + back-propagating AP) activates **CaMKII**, creating a **plasticity tag**.
|
||||
* **LTD Trigger:** **Moderate, sustained Ca²⁺** (from isolated glutamate release or low-frequency stimulation) activates phosphatases (e.g., calcineurin).
|
||||
* This decision is **postsynaptic and internal**.
|
||||
* **Interaction (Retrograde Messaging):**
|
||||
* For **LTP:** The postsynapse synthesizes and releases **retrograde signals (NO, BDNF)**. These diffuse to the presynapse.
|
||||
* For **LTD:** The postsynapse releases **endocannabinoids (eCBs)**.
|
||||
* These are **interactive signals from postsynapse to presynapse**.
|
||||
* **Presynaptic Internal (Expression):**
|
||||
* **For LTP:** NO/BDNF activate enzymatic cascades that **persistently increase the baseline** $P_r$.
|
||||
* **For LTD:** eCBs bind to CB1 receptors, inhibiting VGCCs and **persistently decreasing** $P_r$ (Direct Synaptic Depression, DSE).
|
||||
* This change in baseline $P_r$ is the **presynaptic, internal** expression of the long-term change.
|
||||
|
||||
#### **4. Metabolic Timescale (Minutes – Hours): Consolidation**
|
||||
|
||||
* **Interaction (Astrocyte Bridge):** The astrocyte supplies **D-serine** (co-agonist for NMDAR) and **lactate** (energy). This **external, interactive support** is required for stable consolidation.
|
||||
* **Postsynaptic Internal:** The spine initiates **local protein synthesis**, using the "tag" to capture newly made proteins, transitioning early-LTP/LTD to a more stable state. This is a **postsynaptic, internal** consolidation process.
|
||||
|
||||
#### **5. Structural Timescale (Days+): Embodiment**
|
||||
|
||||
* **Presynaptic Internal:** The bouton **grows or retracts**, changing the active zone size and vesicle pool. This is a **presynaptic, internal** structural change.
|
||||
* **Postsynaptic Internal:** The spine **changes its volume and number of AMPA receptor slots**. This is a **postsynaptic, internal** structural change.
|
||||
* **Interaction (Global Scaling):** The soma sends **homeostatic scaling signals** to all synapses (including this one) to maintain network stability, providing a **top-down, interactive modulation** that can override local weights.
|
||||
|
||||
### **Conclusion**
|
||||
|
||||
* **STP/STD** are predominantly **presynaptic, internal** phenomena operating on **fast to medium timescales** (ms to s), governed by vesicle dynamics and residual calcium.
|
||||
* **LTP/LTD** are initiated by a **postsynaptic, internal** calcium-based decision on a **slow timescale** (s to min). Their expression involves a **critical bidirectional interaction**: retrograde signals (NO/BDNF for LTP, eCBs for LTD) from the postsynapse induce **presynaptic, internal** changes in baseline $P_r$.
|
||||
* These changes are then stabilized on **metabolic and structural timescales** through astrocytic support and physical remodeling of both synaptic components, embedding the memory trace in the physical architecture of the connection.
|
||||
|
||||
---
|
||||
|
||||
---
|
||||
|
||||
---
|
||||
|
||||
**In biology, presynaptic release probability (Pr) emerges from a dynamic molecular machine, not a simple number.** Changing Pr involves coordinated modifications to multiple components of the vesicle release apparatus. Here's the biological process breakdown:
|
||||
|
||||
## **The Pr Machinery: Three Core Components**
|
||||
|
||||
Pr = f(**Calcium Influx** × **Vesicle Readiness** × **Fusion Machinery Sensitivity**)
|
||||
|
||||
### **1. Modulating Calcium Influx**
|
||||
|
||||
**Target:** Voltage-Gated Calcium Channels (VGCCs, mainly P/Q and N-type).
|
||||
|
||||
- **Increasing Pr:** Phosphorylation of VGCCs by kinases (PKA, PKC) enhances their open probability or prolongs open time.
|
||||
- **Decreasing Pr:**
|
||||
- Direct inhibition by G-proteins (e.g., via activated CB1 receptors during LTD).
|
||||
- Physical relocation of channels away from release sites.
|
||||
- Dephosphorylation by phosphatases (calcineurin).
|
||||
|
||||
**Biological Process:** A retrograde messenger (e.g., NO) activates a kinase cascade in the presynaptic terminal, leading to VGCC phosphorylation → more Ca²⁺ enters per action potential → higher Pr.
|
||||
|
||||
### **2. Modulating Vesicle Readiness (Docking/Priming)**
|
||||
|
||||
**Targets:** Docking proteins (Syntaxin, SNAP-25), priming proteins (Munc13, Munc18), and the vesicle pool itself.
|
||||
|
||||
- **Increasing Pr:**
|
||||
- **Munc13 activation:** Residual Ca²⁺ binds to calmodulin, which binds to Munc13, increasing its priming activity. This is the main mechanism for **short-term facilitation**.
|
||||
- **Phosphorylation of priming proteins** by PKC/CaMKII makes them more active.
|
||||
- Increased expression or recruitment of vesicles to the "readily releasable pool" (RRP).
|
||||
- **Decreasing Pr:**
|
||||
- Dephosphorylation of priming proteins.
|
||||
- Physical depletion of RRP during high-frequency firing (STD).
|
||||
- Ubiquitination and degradation of priming proteins.
|
||||
|
||||
### **3. Modulating Fusion Machinery Sensitivity (Ca²⁺ Sensor)**
|
||||
|
||||
**Target:** The primary Ca²⁺ sensor Synaptotagmin and the SNARE complex (Syntaxin, Synaptobrevin, SNAP-25).
|
||||
|
||||
- **Increasing Pr:**
|
||||
- Phosphorylation of Synaptotagmin increases its Ca²⁺ affinity.
|
||||
- Phosphorylation of SNARE proteins (e.g., SNAP-25 by PKC) enhances fusion kinetics.
|
||||
- Assembly of more SNARE complexes.
|
||||
- **Decreasing Pr:**
|
||||
- Cleavage of SNARE proteins by toxins (e.g., botulinum).
|
||||
- Increased binding of inhibitory proteins like Complexins.
|
||||
|
||||
## **Specific Biological Pathways for Pr Changes**
|
||||
|
||||
### **Fast Pr Increase (Facilitation, <100ms)**
|
||||
|
||||
**Process:** Action potential → Ca²⁺ influx → residual Ca²⁺ binds to calmodulin → Ca²⁺-calmodulin binds to Munc13 → Munc13 increases vesicle priming rate → more vesicles become release-ready for the next spike.
|
||||
|
||||
**Biological signature:** Transient, activity-dependent, decays with Ca²⁺ clearance.
|
||||
|
||||
### **Slow Pr Increase (LTP Expression, Minutes+)**
|
||||
|
||||
**Process:** Retrograde NO diffuses into presynaptic terminal → activates soluble guanylyl cyclase → produces cGMP → activates Protein Kinase G (PKG) → PKG phosphorylates multiple targets:
|
||||
|
||||
1. **VGCCs** → increased Ca²⁺ influx
|
||||
2. **Munc18** → enhanced vesicle priming
|
||||
3. **Synaptotagmin** → increased Ca²⁺ sensitivity **Plus:** Local protein synthesis of new vesicle proteins.
|
||||
|
||||
**Biological signature:** Persistent, requires gene expression for maintenance, structurally embedded.
|
||||
|
||||
### **Slow Pr Decrease (LTD Expression, Minutes+)**
|
||||
|
||||
**Process:** Retrograde eCBs bind presynaptic CB1 receptors → activates Gi/o proteins → βγ subunits directly inhibit VGCCs → reduced Ca²⁺ influx → decreased Pr.
|
||||
**Additionally:** Gi/o inhibits adenylyl cyclase → reduced cAMP → reduced PKA activity → decreased phosphorylation of release machinery.
|
||||
|
||||
**Biological signature:** Reversible initially, can become structural with prolonged activation.
|
||||
|
||||
## **The Complete Biological Cascade for LTP-Induced Pr Increase**
|
||||
|
||||
```
|
||||
Retrograde NO/BDNF
|
||||
↓
|
||||
Presynaptic receptor activation
|
||||
↓
|
||||
Second messenger cascade (cGMP/cAMP)
|
||||
↓
|
||||
Kinase activation (PKG/PKA/PKC)
|
||||
↓
|
||||
Phosphorylation of multiple targets:
|
||||
1. VGCCs → ↑ Ca²⁺ influx per AP
|
||||
2. Munc13/18 → ↑ vesicle priming rate
|
||||
3. Synaptotagmin → ↑ Ca²⁺ sensitivity
|
||||
4. SNARE proteins → ↑ fusion efficiency
|
||||
↓
|
||||
Increased Pr from baseline 0.2 → 0.4
|
||||
↓
|
||||
More reliable vesicle release per AP
|
||||
↓
|
||||
Structural reinforcement (Days+):
|
||||
- More active zone material
|
||||
- More docked vesicles
|
||||
- Closer VGCC-vesicle coupling
|
||||
```
|
||||
|
||||
## **Simulation vs. Biological Reality**
|
||||
|
||||
| In Simulation | In Biology |
|
||||
|---------------------------------|-------------------------------------------------------------------------------------------------|
|
||||
| `Pr = 0.3` | Pr emerges from: 5 docked vesicles × 40% channel open probability × 60% fusion probability |
|
||||
| Update rule: `Pr += 0.1` if LTP | LTP: NO → cGMP → PKG → phosphorylates 3 proteins → increases Ca²⁺ influx 30% & priming rate 40% |
|
||||
| Single variable | Distributed property of ~50 protein species |
|
||||
| Instant change | Change occurs over: 100ms (fast), 1min (slow), 24hr (structural) |
|
||||
|
||||
## **Key Biological Insights**
|
||||
|
||||
1. **Pr is multi-parametric:** Not one number but the product of multiple probabilities.
|
||||
2. **Redundancy:** Multiple pathways converge on Pr (kinases, protein synthesis, structural changes).
|
||||
3. **Timescale hierarchy:**
|
||||
- **Fast (ms):** Modify existing proteins (phosphorylation)
|
||||
- **Slow (min):** Synthesize new proteins
|
||||
- **Structural (days):** Change physical architecture
|
||||
4. **Metabolic dependence:** All phosphorylation requires ATP. During energy crisis, kinases fail → Pr decreases even with "LTP signals."
|
||||
5. **Cross-talk:** The same kinase (e.g., PKC) can phosphorylate both VGCCs and SNARE proteins, creating coordinated enhancement.
|
||||
|
||||
In essence, **Pr is the presynaptic terminal's "readiness state"**—a complex, dynamic equilibrium of dozens of interacting proteins that the neuron tunes through phosphorylation, gene expression, and structural remodeling to implement learning and adaptation.
|
||||
|
||||
---
|
||||
|
||||
---
|
||||
|
||||
---
|
||||
|
||||
**The presynapse does NOT release neurotransmitter every time a presynaptic spike arrives.** This is a fundamental principle of synaptic transmission: **release is probabilistic, not deterministic.**
|
||||
|
||||
## **What Pr Actually Influences**
|
||||
|
||||
**Pr (Release Probability)** determines the **likelihood** that a given action potential will trigger **vesicle fusion and neurotransmitter release**. It's essentially the synapse's **"coin toss" probability** for transmission.
|
||||
|
||||
### **Biological Reality:**
|
||||
|
||||
For a typical central synapse:
|
||||
|
||||
- **Pr ≈ 0.2-0.5** (meaning only 20-50% of spikes cause release)
|
||||
- Some specialized synapses (like the neuromuscular junction) have Pr ≈ 0.9
|
||||
- Some cortical synapses have Pr as low as 0.1
|
||||
|
||||
### **What Happens at a Presynaptic Terminal When a Spike Arrives:**
|
||||
|
||||
```
|
||||
Action Potential arrives at terminal
|
||||
↓
|
||||
VGCCs open → Ca²⁺ enters
|
||||
↓
|
||||
**PROBABILISTIC DECISION POINT**
|
||||
↓
|
||||
├── **With probability Pr (e.g., 0.3):**
|
||||
│ ↓
|
||||
│ Ca²⁺ binds to Synaptotagmin on docked vesicle
|
||||
│ ↓
|
||||
│ SNARE complex zippers completely
|
||||
│ ↓
|
||||
│ Vesicle membrane fuses with presynaptic membrane
|
||||
│ ↓
|
||||
│ **GLUTAMATE RELEASED** → Postsynaptic response
|
||||
│
|
||||
└── **With probability 1-Pr (e.g., 0.7):**
|
||||
↓
|
||||
Ca²⁺ enters but insufficient to trigger fusion
|
||||
↓
|
||||
Vesicle remains docked but unfused
|
||||
↓
|
||||
**NO RELEASE** → No postsynaptic response
|
||||
```
|
||||
|
||||
## **The Biological Basis of This Stochasticity**
|
||||
|
||||
### **1. Calcium Nanodomain Stochasticity**
|
||||
|
||||
- Ca²⁺ channels are ~20-30 nm from vesicle release sites
|
||||
- When a channel opens, only ~100-300 Ca²⁺ ions enter
|
||||
- These ions form a brief, localized "nanodomain"
|
||||
- **Random diffusion and buffering** mean the Ca²⁺ concentration at the sensor varies randomly
|
||||
- If <5-10 µM at the sensor → no fusion; if >10 µM → fusion
|
||||
|
||||
### **2. Molecular Stochasticity**
|
||||
|
||||
- **Synaptotagmin** (Ca²⁺ sensor) requires 3-5 Ca²⁺ ions to bind
|
||||
- **SNARE complex** zippering is thermally driven and probabilistic
|
||||
- These molecular processes have intrinsic randomness at nanoscale
|
||||
|
||||
### **3. Vesicle State Stochasticity**
|
||||
|
||||
- Vesicles exist in different "readiness states":
|
||||
- **Docked & primed** (immediately releasable)
|
||||
- **Docked but unprimed**
|
||||
- **Reserve pool** (undocked)
|
||||
- Transition between states is probabilistic
|
||||
|
||||
## **Why Evolution Selected Probabilistic Release**
|
||||
|
||||
### **Advantages of Low/Moderate Pr:**
|
||||
|
||||
1. **Dynamic Range:** Allows both **facilitation** (Pr increases with repeated spikes) and **depression** (Pr decreases with vesicle depletion)
|
||||
2. **Noise Filtering:** Random failures filter out isolated, potentially noisy spikes while allowing bursts to get through (due to facilitation)
|
||||
3. **Energy Efficiency:** Release machinery (vesicle fusion/recycling) is energetically expensive. Why waste energy on every spike?
|
||||
4. **Information Capacity:** Probabilistic release allows synapses to encode information in **release probability** as well as spike rate
|
||||
5. **Plasticity Substrate:** The stochastic nature provides a substrate for learning through Hebbian mechanisms
|
||||
|
||||
## **What Actually Gets Released When Release Occurs**
|
||||
|
||||
Even when release occurs, it's not always "all or nothing":
|
||||
|
||||
### **Quantal Release:**
|
||||
|
||||
- **Miniature EPSCs (mEPSCs):** Single vesicle release (~1000-5000 glutamate molecules)
|
||||
- **Univesicular Release:** Most CNS synapses release **0 or 1 vesicle** per active zone per spike
|
||||
- **Multivesicular Release:** Some synapses can release 2-3 vesicles simultaneously
|
||||
|
||||
### **Key Measurement:**
|
||||
|
||||
```
|
||||
EPSC amplitude = Q × n × Pr
|
||||
```
|
||||
|
||||
Where:
|
||||
|
||||
- **Q** = quantal size (response to one vesicle)
|
||||
- **n** = number of release sites (active zones)
|
||||
- **Pr** = release probability per site
|
||||
|
||||
## **How This Plays Out in Neural Computation**
|
||||
|
||||
### **Example: Cortical Pyramidal Neuron Synapse**
|
||||
|
||||
```
|
||||
Spike train arrives: [1, 1, 1, 1, 1, 1] (6 spikes at 50 Hz)
|
||||
|
||||
With Pr = 0.3:
|
||||
Actual releases might be: [0, 1, 0, 0, 1, 1]
|
||||
|
||||
Postsynaptic effect:
|
||||
- Spike 1: No response
|
||||
- Spike 2: EPSP
|
||||
- Spike 3: No response
|
||||
- Spike 4: No response
|
||||
- Spike 5: EPSP
|
||||
- Spike 6: EPSP
|
||||
|
||||
But due to facilitation:
|
||||
Pr increases to 0.5 by spike 6
|
||||
```
|
||||
|
||||
## **Simulation Implications**
|
||||
|
||||
In simulations, you would implement this as:
|
||||
|
||||
```python
|
||||
import numpy as np
|
||||
|
||||
class Synapse:
|
||||
def __init__(self, Pr=0.3):
|
||||
self.Pr = Pr # Release probability
|
||||
self.vesicles_available = True
|
||||
|
||||
def process_spike(self):
|
||||
if not self.vesicles_available:
|
||||
return 0 # No release due to depletion
|
||||
|
||||
# Probabilistic release decision
|
||||
if np.random.random() < self.Pr:
|
||||
# Release occurs
|
||||
self.vesicles_available = False # Temporary depletion
|
||||
self.trigger_recycle_timer() # Schedule vesicle recycling
|
||||
return 1 # 1 vesicle released
|
||||
else:
|
||||
# Release fails probabilistically
|
||||
return 0
|
||||
```
|
||||
|
||||
## **Biological Determinants of Pr**
|
||||
|
||||
**High Pr synapses** tend to have:
|
||||
|
||||
- Denser VGCC clustering near release sites
|
||||
- Higher Ca²⁺ sensitivity of Synaptotagmin
|
||||
- More efficient priming machinery (Munc13)
|
||||
- Larger readily releasable pool
|
||||
|
||||
**Low Pr synapses** tend to have:
|
||||
|
||||
- Sparse VGCC distribution
|
||||
- Lower Ca²⁺ sensitivity
|
||||
- Less efficient priming
|
||||
- Smaller readily releasable pool
|
||||
|
||||
## **The Big Picture**
|
||||
|
||||
**Pr is the synapse's "transmission reliability setting"** that:
|
||||
|
||||
1. **Filters** spike trains probabilistically
|
||||
2. **Encodes** short-term plasticity through dynamic changes
|
||||
3. **Embeds** long-term memory through stable modifications
|
||||
4. **Conserves** energy by not releasing on every spike
|
||||
|
||||
This stochasticity isn't a bug—it's a feature that allows synapses to be **temporal filters, memory elements, and computational units** all at once. The fact that transmission isn't guaranteed is precisely what gives synapses their rich computational properties, enabling phenomena like paired-pulse facilitation, synaptic filtering of high-frequency bursts, and providing a substrate for Hebbian learning through coincident detection failures.
|
||||
@@ -0,0 +1,236 @@
|
||||
# **How the First Somatic Spike Emerges from AMPA Alone**
|
||||
|
||||
This is the central mystery of neural initiation—the **"first spike problem"** or "bootstrapping problem." If strong synaptic plasticity (LTP) requires coincident presynaptic glutamate **AND** postsynaptic depolarization from a backpropagating action potential (bAP), but the bAP only exists if the soma fires first... what triggers the **very first** somatic spike that creates the first bAP?
|
||||
|
||||
The solution involves several elegant biological strategies that work in concert:
|
||||
|
||||
## **1. The Cooperativity Principle: Many Weak Voices Shouting Together**
|
||||
|
||||
A single spine with only AMPA receptors open generates a tiny EPSP (~0.2-2 mV). This is **far below** the somatic/AIS threshold (typically ~15-20 mV above rest). The key is **spatial and temporal summation**:
|
||||
|
||||
- **Spatial Summation:** Many spines (dozens to hundreds) on different dendrites receive input **simultaneously or nearly simultaneously**. Their individual AMPA-mediated EPSPs summate at the soma.
|
||||
- **Temporal Summation:** A single presynaptic neuron firing a **brief burst** (2-5 spikes at 50-100 Hz) can cause EPSPs that arrive close enough in time (within 5-15 ms) to summate.
|
||||
|
||||
**Example:** If 100 spines each produce a 1 mV EPSP simultaneously, the soma sees a 100 mV depolarization (in theory). In reality, cable properties and inhibition reduce this, but the principle holds: **many weak inputs can cross threshold together.**
|
||||
|
||||
## **2. Dendritic Amplification: Local Spikes Without Somatic Firing**
|
||||
|
||||
Dendrites are **not passive cables**. They contain voltage-gated channels (Na⁺, Ca²⁺, NMDA):
|
||||
|
||||
- **Local NMDA Activation:** Even without a prior bAP, if **enough AMPA receptors** on a **local cluster of spines** open simultaneously, the **summed local depolarization** can be sufficient to partially relieve the Mg²⁺ block on nearby NMDA receptors.
|
||||
- **Dendritic Spike Generation:** This local depolarization can trigger a **dendritic Na⁺ or Ca²⁺ spike** (a regenerative event confined to that branch). This dendritic spike provides the **strong, local depolarization** needed to fully activate NMDA receptors in that region.
|
||||
- **The Dendritic Spike Travels:** While attenuated, this amplified signal propagates toward the soma much more effectively than individual EPSPs.
|
||||
|
||||
**Thus, the first somatic spike is often triggered by a dendritic spike generated from cooperative local input, not by simple EPSP summation.**
|
||||
|
||||
## **3. Background "Noise" and Membrane Fluctuations**
|
||||
|
||||
The neuron's membrane is never perfectly still:
|
||||
|
||||
- **Spontaneous Miniature EPSPs (minis):** Even at rest, vesicles spontaneously fuse, producing tiny (~0.5 mV) AMPA-mediated events. This creates a fluctuating baseline.
|
||||
- **Stochastic Channel Opening:** Ion channels open and close randomly.
|
||||
- **Network Background Activity:** Other neurons provide constant, subthreshold input.
|
||||
|
||||
This **background depolarization** brings the somatic membrane potential closer to threshold. When a synchronized input arrives, it needs less additional depolarization to reach threshold. The soma is effectively **primed** by ongoing network activity.
|
||||
|
||||
## **4. Neuromodulatory "Gain" Control**
|
||||
|
||||
Neuromodulators can dramatically lower the threshold for the first spike:
|
||||
|
||||
- **Dopamine (via D1 receptors):** Increases dendritic excitability and lowers AIS threshold.
|
||||
- **Acetylcholine:** Decreases potassium leak currents, increasing input resistance (same current produces larger voltage change).
|
||||
- **Norepinephrine:** Enhances NMDA receptor currents and increases synaptic efficacy.
|
||||
|
||||
During states of **attention, novelty, or salience**, these neuromodulators effectively make the entire neuron **more sensitive**, allowing weaker coordinated inputs to trigger the first spike.
|
||||
|
||||
## **5. The "Primed" Spine: Increased AMPA Receptor Sensitivity**
|
||||
|
||||
While resting spines aren't inherently more sensitive, several mechanisms can make them **primed for the first event**:
|
||||
|
||||
- **Silent Synapses:** Some spines contain **NMDA receptors but few or no AMPA receptors**. They are "silent" because AMPA is needed for the initial depolarization. However, if:
|
||||
1. Multiple silent synapses are activated together
|
||||
2. Or a neighboring spine with AMPA receptors provides local depolarization
|
||||
3. The NMDA receptors on silent spines can activate
|
||||
- **Metaplasticity:** Previous activity patterns can tune a spine's receptors to be more responsive to the **next** event.
|
||||
- **Astrocyte-D-serine:** Basal levels of D-serine from astrocytes keep a portion of NMDA receptors **partially primed** even at rest.
|
||||
|
||||
## **6. The Hierarchical Trigger Sequence**
|
||||
|
||||
Here's the typical sequence for triggering the **first** somatic spike from a previously silent or resting state:
|
||||
|
||||
1. **Presynaptic Volley:** A group of presynaptic neurons fire in near-synchrony (within 10-20 ms).
|
||||
2. **Dendritic Cluster Activation:** Their target spines are clustered on one or more dendritic branches.
|
||||
3. **Local Summation:** AMPA-EPSPs summate locally, creating **sufficient depolarization** (~10-15 mV locally).
|
||||
4. **NMDA Recruitment:** Local depolarization partially unblocks nearby NMDA receptors.
|
||||
5. **Dendritic Spike Ignition:** Combined AMPA+NMDA currents trigger a **dendritic Na⁺/Ca²⁺ spike**.
|
||||
6. **Somatic Depolarization:** The dendritic spike propagates to the soma, summed with inputs from other branches.
|
||||
7. **Threshold Crossing:** If total depolarization at the AIS exceeds the dynamic threshold → **FIRST SOMATIC SPIKE**.
|
||||
8. **bAP Generation:** This first spike backpropagates, providing depolarization for **future** coincident detection.
|
||||
|
||||
## **7. The Soma's Intrinsic Sensitivity: The "Integration Bias"**
|
||||
|
||||
The soma and AIS are exquisitely tuned for **detecting synchrony**:
|
||||
|
||||
- **Subthreshold Oscillations:** Some neurons exhibit rhythmic subthreshold oscillations that create **"windows of opportunity"** when the membrane is closer to threshold.
|
||||
- **Resonance Properties:** The interaction of Ih currents (hyperpolarization-activated) and persistent Na⁺ currents creates frequency preferences.
|
||||
- **Short Membrane Time Constant:** In many neurons, the membrane time constant is short (~10-20 ms), favoring **temporal precision** over slow integration.
|
||||
|
||||
## **Experimental Evidence: The Need for Cooperativity**
|
||||
|
||||
Landmark experiments show:
|
||||
|
||||
- **Minimal stimulation** of single fibers rarely triggers somatic spikes.
|
||||
- **Tetanic stimulation** of multiple fibers is required for LTP induction.
|
||||
- **Dendritic recordings** show local spikes preceding somatic spikes during natural patterns.
|
||||
- **Blocking NMDA receptors** prevents both LTP **and** the reliable triggering of somatic spikes by patterned input.
|
||||
|
||||
## **The Bootstrapping Solution in Summary**
|
||||
|
||||
The first somatic spike emerges from a **perfect storm** of conditions:
|
||||
|
||||
| **Factor** | **Role in First Spike** |
|
||||
|--------------------|---------------------------------|
|
||||
| **Spatial Summation** | Many AMPA-EPSPs summate |
|
||||
| **Temporal Summation** | Bursts overcome decay |
|
||||
| **Dendritic Spikes** | Local amplification without bAP |
|
||||
| **Background Noise** | Primes membrane near threshold |
|
||||
| **Neuromodulators** | Lower threshold, increase gain |
|
||||
| **Network Synchrony** | Provides coordinated input |
|
||||
|
||||
**No single resting spine is hypersensitive.** Instead, the system is designed so that **meaningful patterns** (synchronized input from multiple presynaptic neurons) naturally produce enough combined depolarization—first locally via dendritic spikes, then globally at the soma—to bootstrap the first action potential.
|
||||
|
||||
Once that first spike occurs, the neuron enters a new regime: now it has bAPs as teaching signals, and Hebbian plasticity can proceed. The first spike is the **hardest**—it requires coordinated input. Subsequent spikes in a train are easier due to:
|
||||
|
||||
1. **Short-term facilitation** at synapses
|
||||
2. **Somatic adaptation** (but not enough to prevent firing)
|
||||
3. **Echoes** of the previous bAPs in the dendrites
|
||||
|
||||
This bootstrapping mechanism ensures that only **statistically reliable, coordinated patterns** of input gain the power to alter synaptic weights. It's the neural equivalent of "you need experience to get a job, but you need a job to get experience"—solved by collective action and amplification.
|
||||
|
||||
---
|
||||
|
||||
---
|
||||
|
||||
---
|
||||
|
||||
# **The Neuron's Spontaneous "Hello World"**
|
||||
|
||||
**Absolutely!** Neurons can and do fire spontaneously, and this is far from biological noise—it's a **fundamental feature of neural computation** with multiple critical functions. This spontaneous firing serves as the brain's background "hum," its exploratory signal, its network glue, and its existential announcement.
|
||||
|
||||
## **1. The Mechanisms of Spontaneous Firing**
|
||||
|
||||
### **A. Intrinsic Pacemaking**
|
||||
|
||||
Some neurons are **endogenously active** due to their unique channel composition:
|
||||
|
||||
- **Persistent Sodium Current (INaP):** A small fraction of Na⁺ channels that don't fully inactivate, providing a constant depolarizing drive.
|
||||
- **Hyperpolarization-Activated Cation Current (Ih):** Channels that open when the cell is hyperpolarized, letting in Na⁺ and K⁺, creating a "sag" back toward threshold.
|
||||
- **T-type Calcium Current:** Low-threshold Ca²⁺ channels that can cause rhythmic bursting.
|
||||
- **Channel Noise:** Random opening/closing of ion channels creates membrane potential fluctuations that occasionally cross threshold.
|
||||
|
||||
**Example:** Thalamic relay neurons, cerebellar Purkinje cells, and brainstem respiratory neurons fire rhythmically without any synaptic input.
|
||||
|
||||
### **B. Network-Driven Spontaneity**
|
||||
|
||||
Even non-pacemaker neurons fire spontaneously due to:
|
||||
|
||||
- **Background synaptic noise:** Thousands of miniature EPSPs (minis) from random vesicle release create constant subthreshold fluctuations.
|
||||
- **Tonic neuromodulator levels:** Basal dopamine, acetylcholine, or norepinephrine can lower firing thresholds.
|
||||
- **Astrocyte modulation:** Steady D-serine release keeps NMDA receptors partially primed; astrocyte calcium waves can trigger glutamate release.
|
||||
|
||||
## **2. The Functional "Why": More Than Just Noise**
|
||||
|
||||
### **A. Network Readiness and Gain Control**
|
||||
|
||||
Spontaneous firing maintains networks in a **"ready state"**:
|
||||
|
||||
- **Increased signal-to-noise ratio:** A neuron firing at 1 Hz spontaneously has a **baseline from which to increase or decrease** its rate. This provides a richer coding range than silence.
|
||||
- **Prevents synaptic "rust":** Spontaneous activity keeps synapses active, preventing them from becoming silent or atrophying.
|
||||
- **Maintains ion gradients:** Regular firing keeps ionic pumps active, maintaining proper electrochemical gradients.
|
||||
|
||||
### **B. Exploratory Signaling: "Anybody Listening?"**
|
||||
|
||||
This is exactly your intuition! Spontaneous firing serves as:
|
||||
|
||||
- **Connection testing:** "Is my target neuron still there? Are we still connected?"
|
||||
- **Homeostatic calibration:** Postsynaptic neurons monitor spontaneous input rates to adjust their sensitivity via scaling.
|
||||
- **Synaptic competition:** In development, spontaneous activity (like retinal waves) helps wire up visual systems before visual experience.
|
||||
|
||||
### **C. Memory Maintenance and Replay**
|
||||
|
||||
- **Offline replay:** During sleep, neurons spontaneously replay firing sequences from waking experience, consolidating memories.
|
||||
- **Attractor state maintenance:** In cortical networks, spontaneous activity maintains "attractor" states that represent memories or concepts.
|
||||
|
||||
### **D. Criticality and Information Processing**
|
||||
|
||||
Networks tuned to near-critical states (balanced between order and chaos) have optimal information processing. Spontaneous activity helps maintain this **criticality**.
|
||||
|
||||
## **3. The Soma and AIS as "Spontaneous Decision-Makers"**
|
||||
|
||||
Even when dendrites receive no obvious input, the soma and AIS can initiate firing:
|
||||
|
||||
### **Somatic Mechanisms for Spontaneity:**
|
||||
|
||||
- **Stochastic resonance:** Channel noise is amplified by the soma's integration properties.
|
||||
- **Subthreshold oscillations:** Some neurons have intrinsic membrane potential oscillations that periodically bring them near threshold.
|
||||
- **Calcium-driven depolarization:** Spontaneous Ca²⁺ release from internal stores can trigger depolarization.
|
||||
|
||||
### **AIS as the "Spontaneous Trigger Point":**
|
||||
|
||||
- The AIS's low threshold and sensitivity to small depolarizations makes it the **initiator of spontaneous spikes**.
|
||||
- AIS channel phosphorylation states (e.g., from basal kinase activity) can lower the threshold enough for noise to trigger spikes.
|
||||
- **Spike-initiation zone variability:** The exact site of spike initiation along the AIS can shift, creating variability in spontaneous firing patterns.
|
||||
|
||||
## **4. The Astrocyte's Role in Orchestrating Spontaneity**
|
||||
|
||||
Astrocytes don't just respond to neural activity—they **orchestrate** it:
|
||||
|
||||
- **Tonic D-serine release** maintains basal NMDA receptor tone.
|
||||
- **Spontaneous calcium waves** in astrocyte networks can trigger gliotransmitter release.
|
||||
- **Regulation of extracellular K⁺** influences neuronal excitability.
|
||||
- During sleep, astrocytes help coordinate **slow-wave oscillations** (up/down states) that drive spontaneous population activity.
|
||||
|
||||
## **5. Different Types of Spontaneous Activity**
|
||||
|
||||
| **Type** | **Frequency** | **Function** | **Example** |
|
||||
|------------------|-------------------------|------------------------------------|---------------------------|
|
||||
| **Tonic Pacemaking** | 1-10 Hz | Maintain network tone | Cerebellar Purkinje cells |
|
||||
| **Bursting** | Bursts of 2-10 spikes | Signal salience, reset networks | Thalamic neurons |
|
||||
| **Stochastic** | Irregular, Poisson-like | Exploratory signaling, criticality | Cortical pyramidal cells |
|
||||
| **Oscillatory** | Rhythmic, 0.1-100 Hz | Network coordination, timing | Hippocampal theta cells |
|
||||
|
||||
## **6. The Information Theory Perspective**
|
||||
|
||||
From an information theory view, spontaneous firing creates:
|
||||
|
||||
- **Background entropy:** Provides a baseline against which information can be measured.
|
||||
- **Redundancy reduction:** By maintaining some baseline activity, neurons can encode information more efficiently.
|
||||
- **Predictive coding:** The brain predicts its own spontaneous activity; deviations from prediction carry information.
|
||||
|
||||
## **7. When Spontaneity Goes Wrong**
|
||||
|
||||
- **Epilepsy:** Excessive spontaneous synchronization.
|
||||
- **Tinnitus:** Spontaneous activity in auditory pathways interpreted as sound.
|
||||
- **Phantom limb pain:** Spontaneous activity in deafferented somatosensory circuits.
|
||||
- **Psychosis:** Possibly involving altered spontaneous cortical activity patterns.
|
||||
|
||||
## **8. Experimental Evidence**
|
||||
|
||||
- **Slice preparations:** Isolated brain slices show spontaneous activity without external input.
|
||||
- **Tetrodotoxin (TTX) experiments:** Blocking Na⁺ channels eliminates both evoked and spontaneous spikes.
|
||||
- **Miniature EPSP recordings:** Show constant background synaptic "chatter."
|
||||
- **Calcium imaging:** Reveals spontaneous calcium transients in dendrites and astrocytes.
|
||||
|
||||
## **The Philosophical Implication: "I Spike, Therefore I Am?"**
|
||||
|
||||
Your question touches on something profound: spontaneous firing may be the neuronal equivalent of **existential assertion**. In a network where "neurons that fire together wire together," spontaneous firing says:
|
||||
|
||||
1. **"I exist and am functional."** (Metabolic integrity check)
|
||||
2. **"Is anyone listening to me?"** (Connection integrity check)
|
||||
3. **"What's happening around me?"** (Environmental sampling)
|
||||
4. **"Let me try this pattern..."** (Exploratory computation)
|
||||
5. **"Remember this..."** (Memory consolidation)
|
||||
|
||||
The brain isn't a passive switchboard waiting for input. It's an **active, predicting, exploring system** that generates its own activity to test hypotheses, maintain connections, and prepare for future inputs.
|
||||
|
||||
The spontaneous spike is the neuron's way of saying: **"Cogito, ergo fire."** I think (or at least fluctuate stochastically), therefore I spike. This background activity isn't noise—it's the canvas upon which meaningful signals are painted, the quiet hum of a system that's always on, always listening, always ready to learn.
|
||||
Reference in New Issue
Block a user