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ocrampal 4c4cb99711 messo a posto i titoli e iniziato il tun vgcc

2026-05-01 12:38:34 +02:00

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presynapse.md

Qui comprendiamo:

PRESYNAPSE: Presynapse
VGCC-PRE: Voltage-Controlled Gated Channels

PRESYNAPSE: Container

Simplified Behaviors:

— ms:

AP fires → VGCCs open, Ca²⁺ enters, based on eCB e mGluR
Ca²⁺ cleared slowly (single decay term, no pump detail)
Ca²⁺ trace (Tr_Ca) integrates every ms
NT released into cleft — rate determined by Ca²⁺ level and NT already in cleft
NT released accumulates (feeds sec behavior)
NT passively diffuses out of cleft
Observed behaviors: -- STD: exhaustion of NT momentarly stops presynapse from releasing NT -- STP: Ca2+ left in the presynapse beteween spikes primes next NT release.

— seconds:

Astrocyte EAATs clear 30% of remaining NT in the cleft (Atrocyte behavior)
eCB retrograde signal updates from postsynapsis (postsynaptic input)
eCB suppresses NT release (feeds back into ms behavior release rate)
RP → RRP recruitment runs (rate gated by Tr_Ca)
NT released in sec resets to zero

— mins:

Glucose level sets base conversion_efficiency (Atrocyte behavior)
If astrocyte wave was triggered → conversion_efficiency boosted temporarily
Glutamine shuttle refills NT reserve from astrocyte store (faster if wave active, baseline if not)
Wave boost decays back to baseline over subsequent cycles

G expression:

Qui riportiamo la struttura della espressione G e una descrizione di come leggerla (uno dei possibili modi):

i possibili behavior della presynapsi sono espressi in due contesti. AP_ctx and NOT AP_ctx. I possibili behavior sono anche raggrupati in ms, sec e min, per facilitarne la verifica. Quello che conta sono gli RF specifici di ciascuno snipplet.
AP-ctx: all'arrivo di un AP dal SOMA:
- si aprono i canali ionici VGCC. Il numero di VGCC e' soggetto a tuning a medi termine.
- i VGCC fanno entrare ioni Ca2+ nella Presynapse, in base a:
  - quanto Ca2+ e' gia' presente (proxy per CDI)
  - alla concentrazione di eCB (che arriva dalla Postsynapse e tende a limitare l'ingresso di Ca2+ per limitare indirettamente il rilascio di NT)
  - alla concentrazione di NT (proxy per mGlur)
- il rilascio di NT avviene in base:
  - alla concetrazione di Ca2+
  - alla concentrazione di Rrp (readily release pool)
- l'accumulo di CaTraces avviene durante AP_ctx. Qui cerchiamo di catturare il livello medio che raggiunge Ca2+ durante varie spike. Non lo possiamo catturare in NOT AP_ctx perche' li facciamo clearance.
NOT AP_ctx: quando la presynapsi e' in fase di "riposo" fra AP facciamo pulizia. Questo riposo e' inter AP non quello alla fine di uno spike train:
- eCB clearance
- Ca2+Traces clearance
- RPShuttle
- RefillRPGlutamine (sec)

# G expression

PRESYNAPSE
  AP_ctx
    ms
      NTreleaseHigh: interacting 
      NTreleaseMedium: interacting
      NTreleaseLow: interacting
      AP-CaClearanceHigh: interacting
      AP-CaClearanceMedium: interacting

  NOT AP_ctx:
    ms
      NotAP-CaClearance: interacting
      CaTracesAccumulationFast: interacting
      CaTracesAccumulationSlow: interacting
      CaTracesClearance: interacting
    sec
      eCBClearance: interacting
      RPShuttleLow: interacting
      RPShuttleMedium: interacting
      RPShuttleHigh: interacting
    min
      Refill RP from Glutamine

VGCC-PRE
  AP_ctx
    ms
      Ca2+enterLow: interacting
      Ca2+enterMedium: interacting
      Ca2+enterHigh: interacting

Tubs:

Ca2+: Calcium Ion entering the Presynapse when VCGG open that influence NT release. Normally returns to ~0 between spikes; stays elevated when pumps fail. They are key to check the concentration, release NT and modulation
Rrp: Readily Releasable Pool: The Readily Releasable Pool consists of the vesicles that are "docked" and "primed" at the active zone of the synapse. 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. Here we consider them as NT ready to be released.
Rp: Reserve Pool: The bulk of the vesicles held further back in the terminal, often tethered by a protein called synapsin. These are only mobilized during intense, prolonged stimulation. This makes up the vast majority of the vesicles (up to 80% or 90%). Here we consider them NT in reserve that can be transfered to RRP and created using Glutamine from Astorcyte.
NT: Neuro Transmitter, released in the synapse by the vescicles. The release increses NT and decreases RRP
CaTraces: sono le tracce di permanenza della concentrazione di Ca2+. Servono alla modulazione (TUN)
eCB: retrograde signal updates from postsynapsis (postsynaptic input)

container: PRESYNAPSE

  expansion: VGCC-PRE ( full: 10x, active: 5x, empty: 2x )

  tub_local:
    - Ca2+ ( full: 60x, active: 30x, empty: 0x )
       # developed_by: DEV-PRE-CA2+FULL from DEV.N
    - Rrp ( full: 30x, active: 15x, empty: 0x )
       # developed_by: DEV-PRE-RRP-FULL from DEV.N
    - Rp ( full: 30x, active: 15x, empty: 0x )
       # developed_by: DEV-PRE-RRP-FULL from DEV.N
    - CaTraces ( full: 50x, active: 0x, empty: 0x )

  tub_intricated:
    - NT ( contained_by: SYN ) 
    - ATP ( contained_by: ? ) 
    - eCB ( contained_by: POST ) 

  context_intricated:
  - AP ( contained_by: SOMA )

AP_ctx: PRESYNAPSE

NTreleaseLow: int: ms

Il rilascio di NT lo facciamo nel contesto di AP. Biologicamente dovrebbe avvenire solo in base alle concentrazioni, quindi anche al difuori degli AP.

RF di interacting deve essere MOLTO piu' basso di un RF di AP. In maniera da essere attivo varie volte nel contesto di un episodio di AP. Il che ha senso perche' un AP e' SOMA ad un tempo piu' alto che i comportamenti di PRE. Questo poi per permettere la diversa contestualizzazione degli episodi di NTrelease, a piu' o meno alta velocita'.

Non consideriamo le vesicles come liberate, ma direttamente gli NT. Questo permette di gestire la quantita' rilasciata di NT, invece di gestire un numero di vescicles. Nella realta' ciascuna vesicle contiene migliaia di NT. Qui mettiamo un floor a questo tipo di comprensione.

Ci sono 4 casi che dipendono da RRP, Ca2+ e indirettamente da concentrazione di NT nella SYN che diventa mGLur che limita in VGCC l'entrata di Ca2+. L'idea e' che la quantita' di RRP sia il driver principale. Gli NT liberati sono di piu' al crescere di RRP e Ca2+ e di meno (indirettamente) al crescere della concentrazione di NT gia' liberati nella SYN. Gli NT nella sinapsi fanno da moderazione alla ulteriore liberazione di NT, ma non bloccano mai totalmente. NT suppression only matters when everything else is already at maximum, which is exactly the biological purpose: it prevents runaway release during peak activity, not during moderate activity.

NT empty. Qui siamo contestualizzati se Ca2+ full, il che dovrebbe significare indirettamente che non ci sono NT nella SYN.

In tutti i casi di NT

interacting: NTreleaseLow
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 12x ) # Low

  hypothesis: ( Ca2+ mediumness ) AND 
              ( Rrp mediumness ) AND
              NOT( ATP empty )
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

NTreleaseMedium: int: ms

In tutti i casi di NT

interacting: NTreleaseMedium
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 9x ) # Medium

  hypothesis: (( Ca2+ fullness ) AND ( Rrp mediumness ) OR 
              ( Ca2+ mediumness ) AND ( Rrp fullness )) AND
              NOT( ATP empty )
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

NTreleaseHigh: int: ms

interacting: NTreleaseHigh
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 3x ) # High

  hypothesis: ( Ca2+ fullness ) AND ( Rrp fullness )  AND 
              NOT( ATP empty )
    action: [Rrp decrease, NT increase, ATP decrease]
    trace: None

Ca2+TracesAccumulationLow: int: ms

Serve a:

fare il tuning dei VGCC
dare la velocita' al trasporto di vesicles da RP a RRP, anche se non avendo ancora compreso ATP, la velocita' non cambia molto la sostanza.
le tracce vengono eliminate quando il neurone e' in pausa, lontano da uno spike train, TunPossible_ctx
Abbiamo 3 tracce, high, medium and low. Andiamo a verificare una combinazione di queste per fare la modulazione
RF e' a 10, questo dovrebbe essere un RF di campionamento durante AP_ctx context che dovremmo assicurarci sia tipo 100. Il che implicherebbe 10 campionamenti.
The biological meaning is that a synapse that has just been through a burst is primed for fast recovery — the molecular machinery for vesicle docking is already engaged, calcium-dependent priming factors are still elevated, and the system is in a ready state. A synapse that has been silent for several seconds has cooled down and replenishes slowly.
So after one second of silence CaTrace has fallen to ~37% of its peak value, after two seconds to ~14%, after three seconds to ~5%. It asymptotes toward zero but never exactly reaches it. Between spikes, Ca2+ falls toward zero as the pumps clear it. The result is that CaTrace encodes not the instantaneous calcium level but the recent history of calcium activity — a smoothed, time-averaged measure of how active the synapse has been over the past one to two seconds.

interacting: Ca2+TracesAccumulationLow
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 10x )

  hypothesis: (Ca2+ emptiness)
    action: [CaTraceLow increase]
    trace: None

Ca2+TracesAccumulationMedium: int: ms

interacting: Ca2+TracesAccumulationMedium
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 10x )

  hypothesis: (Ca2+ mediumness)
    action: [CaTraceMed increase]
    trace: None

Ca2+TracesAccumulationHigh: int: ms

interacting: Ca2+TracesAccumulationHigh
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 10x ) # high

  hypothesis: (Ca2+ fullness)
    action: [CaTraceHigh increase]
    trace: None

NOT AP_ctx: PRESYNAPSE

eCB clearance: int: ms

eCB dipende da POST. Tende a modulare l'entrata di Ca2+ degli VGCC.

Qui non facciamo un flush di eCB, riduciamo ogni mezzo secondo (context) di un RF di questo episodio.

interacting: eCBClearance
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 24x ) # Slow

  hypothesis: NOT (eCB empty)
    action: [eCB decrease]
    trace: None

RPShuttleLow: int: sec

This happens in the seconds loop, once per second.

The "Hard Bottleneck" State. Recruitment is throttled by a lack of signal, a lack of supply, or a lack of space. If even one of these "Near-Stop" conditions is met, the rate cannot exceed "Slow," regardless of the other two conditions.

Rate: 0.00 – 0.25

interacting: RPShuttleLow
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 48x ) # Low

  hypothesis: (CaTraceLow fullness) OR 
              (RP emptiness) OR 
              (RRP fullness)  
    action: [RP decrease, RRP increase]
    trace: None

RPShuttleMedium: int: sec

The "Sub-Optimal" State. The machinery is working, but it's held back by partial limitations. This covers cases where the signal is steady but the "piston" isn't firing at full speed, or where a high vacancy in the RRP (emptiness) forces a low signal to work a bit harder.

Rate: 0.50 – 0.97

interacting: RPShuttleMedium
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 24x ) # Medium

  hypothesis: (CaTraceMedium fullness) AND (RP mediumness) AND (RRP mediumness) OR 
              (CaTraceHigh fullness) AND (RP mediumness) AND (RRP mediumness) OR # signal boost
              (CaTraceMedium fullness) AND (RP fullness) AND (RRP mediumness) OR # supply boost
              (CaTraceMedium fullness) AND (RP mediumness) AND (RRP emptiness) # vacancy boost
    action: [RP decrease, RRP increase]
    trace: None

RPShuttleHigh: int: sec

The "High Performance" State. Multiple systems are optimized, but one is still at a "mediumness" level. This represents an active synapse that hasn't reached its absolute peak because either the supply is only 50% or the RRP isn't empty enough to create that "maximal vacuum" pull.

Rate: 1.25 – 1.94

interacting: RPShuttleHigh
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 12x ) # Fast

  hypothesis: (CaTraceHigh fullness) AND (RP fullness) AND (RRP mediumness) OR # signal + supply
              (CaTraceHigh fullness) AND (RP mediumness) AND (RRP emptiness) OR # signal + vacancy
              (CaTraceMedium fullness) AND (RP fullness) AND (RRP emptiness) # supply + vacancy
    action: [RP decrease, RRP increase]
    trace: None

RefillRPGlutamine: int: min

This happens in the minutes loop, once per minute, via the glutamine shuttle from the astrocyte. It is a two-step process across two cells.

Step 1 — astrocyte side The astrocyte has been accumulating cleared glutamate from the cleft since the last minutes-loop execution. Its glutamine synthetase enzyme converts that glutamate into glutamine, filling the Glutamine_pool. The fraction successfully converted per cycle is conversion_efficiency, which is set by glucose availability and boosted temporarily if the astrocyte calcium wave fired during the preceding seconds:

refill_RP = Glutamine_pool * conversion_efficiency Glutamine_pool = max(0.0, Glutamine_pool - refill_RP)

Step 2 — presynapse side

The glutamine crosses into the presynapse, where glutaminase converts it back into glutamate. That glutamate is immediately repackaged into vesicles and added to N_RP:

The asymmetry that makes depletion possible:

The chain reveals why sustained high-frequency firing eventually depletes the synapse even with all replenishment mechanisms running.

The RRP holds at most Max_RRP = 20 vesicles. At 20 Hz with strong Ca²⁺, release can draw 2-4 vesicles per spike — potentially exhausting the RRP in under a second. The seconds loop can move vesicles from RP to RRP at a maximum rate of k_rec_fast = 5 /s, meaning at most 5 vesicles per second under ideal conditions. Release outpaces recruitment by roughly an order of magnitude during a burst.

The RP holds up to Max_RP = 200 vesicles — ten times the RRP. At sustained 20 Hz the RP can sustain firing for tens of seconds even after the RRP is repeatedly emptied, as long as recruitment keeps pace. But the minutes loop only refills N_RP once per minute at a rate limited by Glutamine_pool * conversion_efficiency. If glucose is low or the astrocyte wave has not fired, this replenishment may add only a fraction of what was consumed.

The result is a three-tier buffer with mismatched timescales:

RRP — depletes in seconds, refilled in seconds (fast but shallow) RP — depletes in minutes, refilled in minutes (deep but slow) Gln — depletes over bursts, refilled by glucose (slowest, astrocyte-dependent)

Each tier buys time for the one below it to respond. When all three are depleted simultaneously — which only happens under prolonged high-frequency firing with insufficient glucose — the synapse has no remaining buffer and goes silent until the minutes loop restores the Glutamine_pool.

TunPossible_ctx: PRESYNAPSE

Ca2+TracesClearance: int: sec

Qui facciamo un flush di CaTraceX.

interacting: Ca2+TracesClearance
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 30x ) # Slow

  hypothesis: NOT (CaTraceHigh empty)
    action: [CaTRaceHigh decrease]
    trace: None

  hypothesis: NOT (CaTraceMedium empty)
    action: [CaTRaceMedium decrease]
    trace: None

  hypothesis: NOT (CaTraceLow empty)
    action: [CaTRaceLow decrease]
    trace: None

VGCC-PRE-TUN: Tuner

tuner: VGCC-PRE-TUN

  # qui stiamo aggiungendo o eliminando VGCC-PRE. Fra un massimo full e minimo empty (empty puo' non essere 0)

  # contained_by: PRESYNAPSE non e' contenuto, si attacca.

  tunes: PRESYNAPSE/expansion/VCGG-PRE

  tub_modulation:
    - VCGG-PRE

  context_intricated:
    - TunPossible_ctx ( contained_by: DAY-N )

  tub_local:

  tub_intricated:

TunPossible_ctx: VGCC-PRE-TUN

CheckVgccPreTun: contexting: sec

Qui controlliamo che ci siano le condizioni per aumentare o diminuire la quantita' di VGCC

contexting: CheckVgccPreTun
  contained_by: VGCC-PRE-TUN

  in_context: TunPossible_ctx
  rf: ( active: 60x )

  condition:  ( CaTraceHigh fullness )
    out_context: TryTunUpPreVcgg_ctx

  condition:  ( CaTraceLow fullness )
    out_context: TryTunDownPreVcgg_ctx

PossibleUpPreVgccTun: int: sec

interacting: PossibleUpPreVgccTun
  contained_by: VGCC-PRE-TUN

  in_context: TryTunUpPreVcgg_ctx
  rf: ( active: 10x )

 hypothesis:  
  action: 
  trace:

PossibleDownPreVgccTun: int: sec

interacting: PossibleDownPreVgccTun
  contained_by: VGCC-PRE-TUN

  in_context: TryTunDownPreVcgg_ctx
  rf: ( active: 10x )

 hypothesis:  
  action: 
  trace:

VGCC-PRE: Container

Voltage-Controlled Gated Channels: Qui per ora non gestiamo l'evoluzione della depolarizzazione. Alla scomparsa dell'AP, i VGCC smettono di funzionare.

container: VGCC-PRE

  tub_intricated:
    - Ca2+ ( contained_by: PRESYNAPSE )
    - NT ( contained_by: SYN )

  context_intricated:
    - AP ( contained_by: SOMA )

AP_ctx: VGCC-PRE

Da rivedere le condizioni per aggiungere mGluR che ha come proxy NT concentration!!!!!

Ca2+enterLow: int: ms

Here we comprehend the breaking activity on VGCC by: CDI, eCB and mGluR:

Qui semplifichiamo:

Approssimiamo CDI con concentrazione di Ca2+. -- CDI is calcium-dependent inactivation of VGCCs. The inactivation happens because Ca²⁺ enters through the channel and binds to a calmodulin tethered to the channel's intracellular face, physically blocking it from reopening. This is a local, channel-specific event — it requires Ca²⁺ to be flowing through that channel right now, not residual Ca²⁺ drifting in the cytosol between spikes. -- The recovery, by contrast, should run every millisecond unconditionally — CDI de-inactivation is a continuous process that proceeds whenever Ca²⁺ dissociates from calmodulin, which depends on the ambient Ca_micro level at all times.
Approssimiamo mGluR con concentrazione NT
Open — zero active brakes. mGluR alone never escapes this group because its ceiling is alpha_mGluR = 0.4, meaning even at full it only removes 40% of conductance, leaving 60% — still above the 85% threshold. So mGluR is irrelevant to the open/not-open boundary. Only CDI and eCB decide.
Reduced/partial — exactly one meaningful brake active. Either CDI has started building (mediumness), or eCB has risen from sustained postsynaptic activity, but not both simultaneously. The system is aware something is happening but has not compounded yet. This is the normal operating range during moderate sustained firing.
Suppressed — two brakes multiplying. The compounding is what defines this zone — no single variable alone produces it (except CDI approaching full). 0.5 × 0.5 = 0.25 remaining is where the synapse starts losing significant transmission efficacy. Biologically this is the pre-silence warning zone: CDI is building from residual Ca²⁺ while eCB is already engaged from postsynaptic activity.
Closed — CDI = full is the only reliable hard rule. Because CDI can reach 1.0 and appears as (1 - CDI_factor) in the formula, it alone drives conductance to zero regardless of eCB and mGluR state. The three-brake overlap corner case (eCB=full + CDI=mediumness + mGluR=full) also reaches here, but in practice CDI reaching full is the primary biological mechanism.

Devo controllare che le condizioni sotto siano esaustive. Qui ho confuso high con low, e inoltre ho messo NT per mGluR che devo controllare che abbia senso.

interacting: Ca2+enterLow
  contained_by: VGCC-PRE

  in_context: AP_ctx
  rf: ( active: 12x ) # Low

  hypothesis: (Ca2+ empty) AND (eCB empty)
    action: [Ca2+ increase, ATP decrease]
    trace: None

Ca2+enterMedium: int: ms

interacting: Ca2+enterMedium
  contained_by: VGCC-PRE

  in_context: AP_ctx
  rf: ( active: 6x ) # Medium

  hypothesis: (Ca2+ mediumness) OR 
              ((eCB mediumness) AND (Ca2+ empty)) OR 
              ((eCB full) AND (Ca2+ empty) AND (NT empty))
    action: [Ca2+ increase, ATP decrease]
    trace: None

Ca2+enterHigh: int: ms

interacting: Ca2+enterHigh
  contained_by: VGCC-PRE

  in_context: AP_ctx
  rf: ( active: 3x ) # High

  hypothesis: (Ca2+ mediumness) AND (eCB full) OR 
              (eCB mediumness)
    action: [Ca2+ increase, ATP decrease]
    trace: None

NOT AP_ctx: VGCC-PRE

Ca2+ClearanceLow: int: ms

Qui eliminiamo Ca2+. Il tempo che ci mette ad eliminare il Ca2+ dovrebbe essere minoe dell'inervallo fra un AP_ctx e un'altra. Siccome non comprendiamo per ora ATP, non c'e' accumulo di Ca2+ per mancanza di ATP (stanchezza).

Non non comprendiamo anche il ristabilimento del Voltage, con altri Ioni entranti e uscenti, per ora tutto dipende da AP del SOMA. Non comprendiamo per ora:

PMCA: primary, ATP-dependent
NCX: fast, NOT ATP-dependent
SERCA: slowest, ATP-dependent

Qui disinguiamo:

Ca+2 fullness che si puo' verificare alla fine di un AP
NOT ca2+ fullness che svuota piu' lentamente
da capire se serve veramente questa distinzione per il tempo di svuotamento.

interacting: Ca2+ClearanceLow
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 24x ) # Low

  hypothesis: (NOT Ca2+ fullness) AND (NOT Ca2+ empty) 
    action: [Ca2+ decrease]
    trace: None

Ca2+ClearanceHigh: int: ms

interacting: Ca2+ClearanceHigh
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 4x ) # High

  hypothesis: NOT (Ca2+ empty)
    action: [Ca2+ decrease]
    trace: None

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