Update README.md
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@@ -98,7 +98,7 @@ The axon does not contain specific behavior. We might add balancing of ATP withi
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### Presynapse
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**Discursive description**:
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#### Discursive description
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The presynapse is the sending terminal of a neuron — a small bulb at the tip of an axon whose job is to release chemical signals, called neurotransmitters (NT), into the synaptic cleft, the narrow gap that separates it from the receiving neuron's postsynapse.
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@@ -116,63 +116,7 @@ The astrocyte is also the gateway to the energy supply. All of the active proces
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The presynapse does not release blindly. Its behaviour is governed by three interlocking closed loops — the NT loop, the Ca²⁺ loop, and the ATP loop — each operating on a different timescale and each feeding back on the others.
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---
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#### VGCC Tuning
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**Short, medium and long time scale**
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1. The Short-Term Mechanism: Local CDI
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On the millisecond scale, CDI is "fast." Each VGCC is physically coupled to a calcium-sensing protein called Calmodulin (CaM).
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1. When a single channel opens, the $Ca^{2+}$ concentration in the immediate vicinity (the nanodomain) can reach $10–100 \mu M$.
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2. This binds to the CaM "sensor," which flips the channel shut.
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3. The Result: This limits the duration of the current $Ca^{2+}$ influx, acting as a high-pass filter.
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2. The Medium-Term Mechanism: Bulk Accumulation
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This is where your ATP loop and Ca2+ loop intersect. If the firing frequency is high, or if the ATP-dependent pumps (PMCA/SERCA) are slowing down, the "bulk" $Ca^{2+}$ in the terminal does not return to baseline between spikes.
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3. Cumulative CDI: As residual $Ca^{2+}$ builds up in the terminal ($Tr\_Ca$ in your model), the CaM sensors on the VGCCs stay partially "primed" or occupied.The
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1. Effect: This means when the next action potential arrives, the channels are already in a semi-inactivated state. Fewer channels are "available" to open, and those that do open close faster.
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2. Timescale: This operates on the scale of hundreds of milliseconds to seconds, effectively mapping the decay curve of your calcium clearance pumps.
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4. Modulation by the "State" of the Channel
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In the minutes and beyond category, the accumulation of $Ca^{2+}$ changes the structural landscape of the VGCCs through two medium-term signals:
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1. A. The "Clogged" Channel Signal (Minutes)
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If $Ca^{2+}$ accumulation is high enough to keep CDI active for a prolonged period (as in your "self-imposed silence" scenario), the channel spends too much time in the inactivated state.
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1. Ubiquitination: Inactivated channels are more susceptible to being tagged by E3 ubiquitin ligases (like Nedd4-1).
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2. Elimination: Once tagged, they are endocytosed (removed from the membrane). This is a medium-term "down-scaling" to prevent excitotoxicity.
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2. B. The Calcineurin Pathway (Minutes to Hours)
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Accumulated $Ca^{2+}$ activates
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1. Calcineurin (PP2B), a phosphatase.Calcineurin dephosphorylates the VGCCs and their anchoring proteins (like RIM).
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2. This physically "loosens" the channels from the Active Zone. They drift away from the release sites, meaning even if they do open, they are too far away from the vesicles to trigger release.
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1. Modeling Summary for your Loops
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If you are building this into your simulation, the Availability ($A$) of VGCCs can be modeled as a function of both the instantaneous spike and the integrated trace:$$A = (1 - CDI_{fast}) \times (1 - f(Tr\_Ca))$$
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1. Short term: $CDI_{fast}$ resets (mostly) between spikes if pumps are healthy.
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2. Medium term: $f(Tr\_Ca)$ grows as ATP drops, locking the "Availability" to near zero.
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3. Long term: If $f(Tr\_Ca)$ stays high for $>X$ minutes, trigger a decrement in the $Total\_VGCC\_Count$ (structural elimination).
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**Long time scale**
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In the minutes-to-hours range, the presynapse shifts from "gating" (turning existing channels on/off) to remodeling (changing the physical number of channels). This process is governed by a shift from purely electrical signals to biochemical "state" signals.The primary signal that dictates the density of VGCCs at the terminal is the history of the $Ca^{2+}$ trace, specifically mediated through three core molecular pathways:
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1. The RIM-Binding Protein (RBP) Scaffold (Minutes)
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The most immediate way to "add" or "eliminate" channels without synthesizing new protein is through lateral mobility. VGCCs aren't bolted down; they are held in place by a scaffold called the Active Zone (AZ), composed of proteins like RIM and Cast.
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1. The Signal: High-frequency activity leads to the phosphorylation of RIM.
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2. The Action: This alters the "slots" available for VGCCs. If RIM is phosphorylated or degraded due to over-activity, it loses its grip on the channel. The VGCC then drifts out of the Active Zone into the "perisynaptic" space.
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3. The Scale: This happens over 5–30 minutes. The channel is still on the membrane, but it's no longer near the vesicles, effectively "eliminating" its influence on neurotransmitter release.
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2. Ubiquitin-Mediated Endocytosis (Minutes to Hours)
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If the "silence" you described in the ATP loop persists, the cell moves from drifting channels to actually removing them from the surface.
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1. The Signal: Ubiquitin ligases (like Nedd4). These enzymes are often activated by prolonged high internal $Ca^{2+}$ or metabolic stress.
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2. The Action: They tag the VGCC protein with a "trash me" label (ubiquitin). This triggers endocytosis, where the membrane folds inward and swallows the channel, moving it into an internal vesicle for degradation.
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3. The Purpose: This is the ultimate "excitotoxic brake." If the ATP loop can’t recover, the cell physically reduces its capacity for $Ca^{2+}$ entry to prevent permanent damage.
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3. Homeostatic Scaling & Gene Expression (Hours to Days)
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When the "silence" lasts for a long time, the neuron assumes the synapse is underperforming and needs more "ears."
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1. The Signal: Nuclear factor of activated T-cells (NFAT) or CREB. These are transcription factors that reside in the synapse but travel to the nucleus when $Ca^{2+}$ levels stay low for too long.
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2. The Action: The nucleus "shships" more VGCC mRNA and protein (specifically the $\alpha_1$ subunit) back down the axon to the terminal.
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3. The Scale: This is the "Minutes and Beyond" territory. It is a slow, structural increase in the total number of channels to restore firing to a baseline level.
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4. Summary of the "Minutes" Signal Logic
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In your three-loop model, the ATP loop is likely the master regulator of these signals:
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1. Low ATP/High Residual $Ca^{2+}$ (Short term): Causes CDI (channels lock shut).
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2. Persistent $Ca^{2+}$ Overload (Minutes): Activates Ubiquitin ligases $\rightarrow$ Physical removal of VGCCs (Elimination).
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3. Chronic Silence/Low $Ca^{2+}$ Flux (Hours): Triggers Homeostatic Scaling $\rightarrow$ Trafficking of new VGCCs to the terminal (Addition).
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---
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**Behaviors**:
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#### Behaviors
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— ms:
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@@ -212,9 +156,7 @@ In your three-loop model, the ATP loop is likely the master regulator of these s
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- conversion_efficiency gates glutamine shuttle throughput
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- Glutamine shuttle refills N_RP from astrocyte store
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---
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**Semplified comprehension**:
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#### Semplified comprehension
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In this comprehension, we decide to simplify:
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@@ -232,10 +174,6 @@ The simplification impies that:
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- Removing ATP removes the metabolic silencing cascade entirely. The mins behavior now only does one thing: replenish the NT reserve. If we want the synapse to still be able to fail under sustained firing, the mechanism would have to come from NT depletion alone (RP exhausted, nothing to replenish) rather than from pump failure and Ca²⁺ accumulation.
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- "Ca²⁺ cleared slowly" replaces PMCA, NCX, and SERCA with a single exponential decay. This means Ca²⁺ will still accumulate under high firing if the decay is slow relative to the spike rate, which preserves some of the residual-Ca²⁺ dynamic even without the full pump machinery.
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---
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---
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**Traditional simplified Behaviors**:
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**— ms:**
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- AP fires → VGCCs open, Ca²⁺ enters, based on eCB e mGluR
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@@ -264,9 +202,7 @@ The simplification impies that:
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(faster if wave active, baseline if not)
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- Wave boost decays back to baseline over subsequent cycles
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---
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**G expression**:
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#### G expression
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Qui riportiamo la struttura della espressione G e una descrizione di come leggerla (uno dei possibili modi):
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- 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.
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@@ -287,83 +223,61 @@ Qui riportiamo la struttura della espressione G e una descrizione di come legger
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- RPShuttle
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- RefillRPGlutamine (sec)
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#### Comportamenti
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#### VGCC Tuning
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uscita NT (Rrp)
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##### Short, medium and long time scale
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1. The Short-Term Mechanism: Local CDI
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||||
On the millisecond scale, CDI is "fast." Each VGCC is physically coupled to a calcium-sensing protein called Calmodulin (CaM).
|
||||
1. When a single channel opens, the $Ca^{2+}$ concentration in the immediate vicinity (the nanodomain) can reach $10–100 \mu M$.
|
||||
2. This binds to the CaM "sensor," which flips the channel shut.
|
||||
3. The Result: This limits the duration of the current $Ca^{2+}$ influx, acting as a high-pass filter.
|
||||
2. The Medium-Term Mechanism: Bulk Accumulation
|
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This is where your ATP loop and Ca2+ loop intersect. If the firing frequency is high, or if the ATP-dependent pumps (PMCA/SERCA) are slowing down, the "bulk" $Ca^{2+}$ in the terminal does not return to baseline between spikes.
|
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3. Cumulative CDI: As residual $Ca^{2+}$ builds up in the terminal ($Tr\_Ca$ in your model), the CaM sensors on the VGCCs stay partially "primed" or occupied.The
|
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1. Effect: This means when the next action potential arrives, the channels are already in a semi-inactivated state. Fewer channels are "available" to open, and those that do open close faster.
|
||||
2. Timescale: This operates on the scale of hundreds of milliseconds to seconds, effectively mapping the decay curve of your calcium clearance pumps.
|
||||
4. Modulation by the "State" of the Channel
|
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In the minutes and beyond category, the accumulation of $Ca^{2+}$ changes the structural landscape of the VGCCs through two medium-term signals:
|
||||
1. A. The "Clogged" Channel Signal (Minutes)
|
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If $Ca^{2+}$ accumulation is high enough to keep CDI active for a prolonged period (as in your "self-imposed silence" scenario), the channel spends too much time in the inactivated state.
|
||||
1. Ubiquitination: Inactivated channels are more susceptible to being tagged by E3 ubiquitin ligases (like Nedd4-1).
|
||||
2. Elimination: Once tagged, they are endocytosed (removed from the membrane). This is a medium-term "down-scaling" to prevent excitotoxicity.
|
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2. B. The Calcineurin Pathway (Minutes to Hours)
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Accumulated $Ca^{2+}$ activates
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1. Calcineurin (PP2B), a phosphatase.Calcineurin dephosphorylates the VGCCs and their anchoring proteins (like RIM).
|
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2. This physically "loosens" the channels from the Active Zone. They drift away from the release sites, meaning even if they do open, they are too far away from the vesicles to trigger release.
|
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1. Modeling Summary for your Loops
|
||||
If you are building this into your simulation, the Availability ($A$) of VGCCs can be modeled as a function of both the instantaneous spike and the integrated trace:$$A = (1 - CDI_{fast}) \times (1 - f(Tr\_Ca))$$
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1. Short term: $CDI_{fast}$ resets (mostly) between spikes if pumps are healthy.
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2. Medium term: $f(Tr\_Ca)$ grows as ATP drops, locking the "Availability" to near zero.
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3. Long term: If $f(Tr\_Ca)$ stays high for $>X$ minutes, trigger a decrement in the $Total\_VGCC\_Count$ (structural elimination).
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ingresso Ca2+
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uscita Ca2+
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ingresso tracceCa2+
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uscita tracceCa2+
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uscita eCb
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ingresso Rrp / uscita Rp
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ingresso Rp
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tuning VGCC
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#### Condizioni
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##### Rilascio NT - comportamento
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Il comportamento principale che assegniamo al container Presinspse e’ quello del rilascio di NT all’arrivo di AP_ctx dal SOMA. Il rilascio di NT all’arrivo di AP_ctx dal SOMA dipende da:
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- Concentrazione di Ca2+
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- Quantita’ di Rrp disponibile
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- ATP disponibile?
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##### Concentrazione di Ca2+ - condizione
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La concentrazione di Ca2+ dipende da:
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##### Ingresso Ca2+ - comportamento
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L’ingresso di Ca2+ avviene tramite i VGCC e dipende da:
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- quantita’ di VGCC
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- CDI
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- eCb
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- ATP?
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##### CDI - Condizione
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Ha un proprio refractory e dipende dalla concentrazione di Ca2+. Normalmente si attiva all’apertura dei VGCC, perche’ deve limitare l’ingresso di Ca2+, che altrimenti entrerebbero come in una cascata. Invece qui si gestisce anche la coincidenza temporale, ovvero AP deve arrivare quando non c’e’ CDI, altrimenti il sistema non funziona efficientemente.
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##### Ristagno Ca2+
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Il ristagno di Ca2+ e’ dovuto:
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- Alla mancanza di ATP che non permette l’eliminazione tramite le pompe
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- La alta frequenza di spike che non permette anche in presenza di ATP di eliminare CA2+
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##### Eliminazione Ca2+
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ATP is consumed continuously by three processes:
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- the Na/K-ATPase pump that restores the membrane gradient after each spike (the largest cost, proportional to firing rate)
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- the PMCA and SERCA pumps that clear Ca²⁺ from the cytosol
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- the molecular machinery that docks and primes vesicles for release.
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These costs accumulate in an ATP demand register that grows with every spike and every Ca²⁺ clearance event in the millisecond loop.
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##### Permanenza di Ca2+ - Trace - medium/long period
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Questo serve per il medio/lungo periodo
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##### Quantita’ di Rrp disponibile
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##### ATP disponibile
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---
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##### Long time scale
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In the minutes-to-hours range, the presynapse shifts from "gating" (turning existing channels on/off) to remodeling (changing the physical number of channels). This process is governed by a shift from purely electrical signals to biochemical "state" signals.The primary signal that dictates the density of VGCCs at the terminal is the history of the $Ca^{2+}$ trace, specifically mediated through three core molecular pathways:
|
||||
1. The RIM-Binding Protein (RBP) Scaffold (Minutes)
|
||||
The most immediate way to "add" or "eliminate" channels without synthesizing new protein is through lateral mobility. VGCCs aren't bolted down; they are held in place by a scaffold called the Active Zone (AZ), composed of proteins like RIM and Cast.
|
||||
1. The Signal: High-frequency activity leads to the phosphorylation of RIM.
|
||||
2. The Action: This alters the "slots" available for VGCCs. If RIM is phosphorylated or degraded due to over-activity, it loses its grip on the channel. The VGCC then drifts out of the Active Zone into the "perisynaptic" space.
|
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3. The Scale: This happens over 5–30 minutes. The channel is still on the membrane, but it's no longer near the vesicles, effectively "eliminating" its influence on neurotransmitter release.
|
||||
2. Ubiquitin-Mediated Endocytosis (Minutes to Hours)
|
||||
If the "silence" you described in the ATP loop persists, the cell moves from drifting channels to actually removing them from the surface.
|
||||
1. The Signal: Ubiquitin ligases (like Nedd4). These enzymes are often activated by prolonged high internal $Ca^{2+}$ or metabolic stress.
|
||||
2. The Action: They tag the VGCC protein with a "trash me" label (ubiquitin). This triggers endocytosis, where the membrane folds inward and swallows the channel, moving it into an internal vesicle for degradation.
|
||||
3. The Purpose: This is the ultimate "excitotoxic brake." If the ATP loop can’t recover, the cell physically reduces its capacity for $Ca^{2+}$ entry to prevent permanent damage.
|
||||
3. Homeostatic Scaling & Gene Expression (Hours to Days)
|
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When the "silence" lasts for a long time, the neuron assumes the synapse is underperforming and needs more "ears."
|
||||
1. The Signal: Nuclear factor of activated T-cells (NFAT) or CREB. These are transcription factors that reside in the synapse but travel to the nucleus when $Ca^{2+}$ levels stay low for too long.
|
||||
2. The Action: The nucleus "shships" more VGCC mRNA and protein (specifically the $\alpha_1$ subunit) back down the axon to the terminal.
|
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3. The Scale: This is the "Minutes and Beyond" territory. It is a slow, structural increase in the total number of channels to restore firing to a baseline level.
|
||||
4. Summary of the "Minutes" Signal Logic
|
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In your three-loop model, the ATP loop is likely the master regulator of these signals:
|
||||
1. Low ATP/High Residual $Ca^{2+}$ (Short term): Causes CDI (channels lock shut).
|
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2. Persistent $Ca^{2+}$ Overload (Minutes): Activates Ubiquitin ligases $\rightarrow$ Physical removal of VGCCs (Elimination).
|
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3. Chronic Silence/Low $Ca^{2+}$ Flux (Hours): Triggers Homeostatic Scaling $\rightarrow$ Trafficking of new VGCCs to the terminal (Addition).
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### Soma
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**Discursive description**:
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#### Discursive description
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The soma is the cell body of the neuron — a roughly spherical structure, typically 10 to 30 micrometres across, that sits at the convergence point of all dendritic branches and at the origin of the axon. It is the decision-making centre of the neuron: its job is to continuously monitor the summed electrical input arriving from the dendrites and decide, moment by moment, whether that input is strong enough to warrant sending a signal forward. That decision takes the form of an action potential — a brief, explosive electrical event that propagates down the axon to the next neuron in the circuit and simultaneously backward up the dendrites as the bAP that enables postsynaptic plasticity.
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@@ -404,7 +318,7 @@ Return to exact -70 mV ~100-1000 ms Na⁺/K⁺ pumps restore gradients
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---
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**Simplified comprehension**:
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#### Simplified comprehension
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In this model we decide to simplify:
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@@ -423,11 +337,9 @@ Removing subthreshold oscillations means VSOMA behaves as a simple leaky integra
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ATP is a simplification of convenience — at this stage we do not comprehend the total metabolic load.
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---
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### Dendritic-branch
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**Discursive description**:
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#### Discursive description
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The dendrite is the receiving arm of a neuron — a long, branching extension of the cell body whose job is to collect the electrical signals generated by postsynaptic spines, integrate them in space and time, and route their combined effect toward the soma, where the decision to fire an action potential is made. A single dendritic branch can be thought of as a shared electrical highway: dozens to hundreds of postsynaptic spines line its length, each one a private compartment where synaptic signals are first detected, and the dendrite shaft is the common conductor that carries all of their contributions forward.
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@@ -447,9 +359,7 @@ The bAP is the bridge that closes the loop between the postsynapse and the dendr
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The dendrite therefore runs three interlocking processes across its timescales. On the millisecond scale, it continuously integrates arriving EPSPs and distributes the bAP to all spines. On the seconds scale, it does not itself perform any active computation — the integration is purely electrical and instantaneous relative to the slower processes happening in the spines and at the soma. On the minutes to hours scale, structural changes driven by plasticity — spine neck widening under LTP, spine retraction under LTD — alter the dendritic geometry and therefore the weighting of individual spines in the summation. The dendrite learns not by changing its own proteins but by changing its shape.
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---
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**Simplified comprehension**:
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#### Simplified comprehension
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In this model we decide to simplify:
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@@ -471,11 +381,9 @@ The only behavior we model:
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- Integrations of spine EPSPs into VDB
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- Uniform bAP distribution to all spines on soma firing. In this case the dendrites acts as a cable, relaying the bAp to Postsynapse. bAp arrives here and directly to each spine, no distance from SOMA and attenuation.
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---
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### Postsynapse
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**Discursive description**:
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#### Discursive description
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The postsynapse is the receiving terminal of a neuron — a specialised patch of membrane on the surface of a dendrite, sitting directly across the synaptic cleft from the presynapse. Its job is to detect the neurotransmitters (NT) released by the presynapse, convert that chemical signal back into an electrical response, and decide — based on the history and pattern of that activity — whether to strengthen or weaken the connection for the future.
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@@ -495,47 +403,7 @@ Like its presynaptic partner, the postsynapse is governed by three interlocking
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The Critical Connection with the presynapse: The system is beautifully asymmetric. While the presynapse is built to **supply** signal, the postsynapse is built to **filter** it.
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---
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**The $V_{post}$ Loop**: The Fast Gatekeeper (Milliseconds)
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This is the primary electrophysiological response, where chemical signals are converted back into electricity.
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- **Activation:** When NT arrives in the cleft, it binds to **AMPA receptors**. These act as the primary current drivers. If `NT_cleft` is **Full** and receptors are not in a **Desensitization** state, the $Na^{+}$ influx causes the local membrane potential ($V_{post}$) to rise steeply.
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- **The bAP Feedback:** The postsynapse does not work in isolation. It receives a **back-propagating Action Potential (bAP)**—an electrical "echo" sent from the cell body whenever the neuron fires.
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- **Coincidence Logic:** On this millisecond scale, the loop computes a logical **AND** operation. If local AMPA-driven depolarization coincides with a somatic bAP, the total $V_{post}$ becomes **Full**. This massive depolarization is the only thing strong enough to kick the magnesium "plug" out of the **NMDA receptors**, allowing the next loop to begin.
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---
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**The $Ca^{2+}$ Loop**: The Plasticity Controller (Seconds)
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This loop translates electrical timing into biological "memory."
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- **The NMDA Gate:** $Ca^{2+}$ entry is strictly gated by the NMDA receptor. Unlike the presynaptic VGCCs (which open with any spike), the NMDA channel only opens if it senses both NT (from the presynapse) and high $V_{post}$ (from the bAP).
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- **Signaling Fate (LTP/LTD):** The amplitude of the $Ca^{2+}$ surge determines the synapse’s fate. A **Full** surge (perfect coincidence) triggers **LTP**, signaling the astrocyte to help strengthen the synapse. A **Medium** or poorly timed surge triggers **LTD**, weakening the connection.
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|
||||
- **Retrograde Signaling (eCB):** If $Ca^{2+}$ levels remain high for too long, the postsynapse synthesizes **endocannabinoids (eCB)**. This signal travels backward across the cleft to tell the presynapse to stop sending NT. This is the primary safety valve that prevents the postsynapse from being overwhelmed.
|
||||
|
||||
---
|
||||
|
||||
**The ATP Loop**: The Metabolic Backbone (Minutes)
|
||||
|
||||
This is the "Hidden Master" that determines if the other two loops are allowed to function.
|
||||
|
||||
- **The Cost of Logic:** The postsynapse is metabolically expensive. The $Na/K$ pumps must work constantly to reset the $V_{post}$ gradient, and the **PMCA pumps** must use ATP to flush out the $Ca^{2+}$ that entered through NMDA channels.
|
||||
|
||||
- **The Astrocyte Bridge:** The astrocyte provides the glucose required to replenish ATP. It also performs a "janitorial" service: it clears excess Potassium ($K^{+}$) and Glutamate from the cleft. If the astrocyte is starved of glucose, the **ATP_level_post** drops to **Empty**.
|
||||
|
||||
- **The False Trigger (Excitotoxic Protection):** When ATP fails, the $Ca^{2+}$ pumps stop. Even without an NMDA surge, $Ca^{2+}$ begins to "leak" and accumulate in the spine. This creates a **False Trigger**: the high $Ca^{2+}$ level initiates eCB synthesis, silencing the presynapse even though there was no "real" signal. This is a desperate survival mechanism; by tricking the presynapse into silence, the postsynapse stops the influx of ions and buys time for its ATP levels to recover.
|
||||
|
||||
The failure of the ATP loop in the postsynapse is arguably more dangerous; if the postsynaptic pumps fail and the eCB "False Trigger" doesn't fire, the spine will literally digest itself from $Ca^{2+}$ overload.
|
||||
|
||||
---
|
||||
|
||||
**Behaviors**:
|
||||
#### Behaviors
|
||||
|
||||
— ms:
|
||||
|
||||
@@ -569,9 +437,7 @@ The failure of the ATP loop in the postsynapse is arguably more dangerous; if th
|
||||
- If Plasticity_LTD tagged → AMPA density decreases
|
||||
- AMPA density feeds back into receptor_conductance ceiling for next cycle
|
||||
|
||||
---
|
||||
|
||||
**Simplified comprehension**:
|
||||
#### Simplified comprehension
|
||||
|
||||
In this comprehension we decide to simplify:
|
||||
|
||||
@@ -584,3 +450,40 @@ The simplification implies that:
|
||||
- Removing ATP removes the false eCB trigger mechanism entirely. The retrograde signal remains but it is always genuine — driven by real Ca_post elevation from NMDA coincidence, not pump failure. The synapse cannot enter the excitotoxic protection cascade.
|
||||
- Removing Desensitization_level means the postsynapse cannot fatigue under sustained NT exposure. Receptor availability is always at maximum, so the tenth burst produces the same AMPA response as the first. This preserves the short-term dynamics of V_post without the adaptation layer.
|
||||
- Removing Ca²⁺ clearance detail means Ca_post reflects the cumulative history of coincidence events with a single decay constant rather than the interplay of PMCA, NCX speed, and ATP availability. Ca_post will still accumulate under high-frequency coincident firing if the decay is slow relative to the event rate, which preserves the eCB trigger dynamic even without the full pump machinery.
|
||||
|
||||
#### The loops
|
||||
|
||||
##### The V_post Loop
|
||||
The Fast Gatekeeper (Milliseconds)
|
||||
|
||||
This is the primary electrophysiological response, where chemical signals are converted back into electricity.
|
||||
|
||||
- **Activation:** When NT arrives in the cleft, it binds to **AMPA receptors**. These act as the primary current drivers. If `NT_cleft` is **Full** and receptors are not in a **Desensitization** state, the $Na^{+}$ influx causes the local membrane potential ($V_{post}$) to rise steeply.
|
||||
|
||||
- **The bAP Feedback:** The postsynapse does not work in isolation. It receives a **back-propagating Action Potential (bAP)**—an electrical "echo" sent from the cell body whenever the neuron fires.
|
||||
|
||||
- **Coincidence Logic:** On this millisecond scale, the loop computes a logical **AND** operation. If local AMPA-driven depolarization coincides with a somatic bAP, the total $V_{post}$ becomes **Full**. This massive depolarization is the only thing strong enough to kick the magnesium "plug" out of the **NMDA receptors**, allowing the next loop to begin.
|
||||
|
||||
##### The Ca2+ Loop
|
||||
The Plasticity Controller (Seconds)
|
||||
|
||||
This loop translates electrical timing into biological "memory."
|
||||
|
||||
- **The NMDA Gate:** $Ca^{2+}$ entry is strictly gated by the NMDA receptor. Unlike the presynaptic VGCCs (which open with any spike), the NMDA channel only opens if it senses both NT (from the presynapse) and high $V_{post}$ (from the bAP).
|
||||
|
||||
- **Signaling Fate (LTP/LTD):** The amplitude of the $Ca^{2+}$ surge determines the synapse’s fate. A **Full** surge (perfect coincidence) triggers **LTP**, signaling the astrocyte to help strengthen the synapse. A **Medium** or poorly timed surge triggers **LTD**, weakening the connection.
|
||||
|
||||
- **Retrograde Signaling (eCB):** If $Ca^{2+}$ levels remain high for too long, the postsynapse synthesizes **endocannabinoids (eCB)**. This signal travels backward across the cleft to tell the presynapse to stop sending NT. This is the primary safety valve that prevents the postsynapse from being overwhelmed.
|
||||
|
||||
##### The ATP Loop
|
||||
The Metabolic Backbone (Minutes)
|
||||
|
||||
This is the "Hidden Master" that determines if the other two loops are allowed to function.
|
||||
|
||||
- **The Cost of Logic:** The postsynapse is metabolically expensive. The $Na/K$ pumps must work constantly to reset the $V_{post}$ gradient, and the **PMCA pumps** must use ATP to flush out the $Ca^{2+}$ that entered through NMDA channels.
|
||||
|
||||
- **The Astrocyte Bridge:** The astrocyte provides the glucose required to replenish ATP. It also performs a "janitorial" service: it clears excess Potassium ($K^{+}$) and Glutamate from the cleft. If the astrocyte is starved of glucose, the **ATP_level_post** drops to **Empty**.
|
||||
|
||||
- **The False Trigger (Excitotoxic Protection):** When ATP fails, the $Ca^{2+}$ pumps stop. Even without an NMDA surge, $Ca^{2+}$ begins to "leak" and accumulate in the spine. This creates a **False Trigger**: the high $Ca^{2+}$ level initiates eCB synthesis, silencing the presynapse even though there was no "real" signal. This is a desperate survival mechanism; by tricking the presynapse into silence, the postsynapse stops the influx of ions and buys time for its ATP levels to recover.
|
||||
|
||||
The failure of the ATP loop in the postsynapse is arguably more dangerous; if the postsynaptic pumps fail and the eCB "False Trigger" doesn't fire, the spine will literally digest itself from $Ca^{2+}$ overload.
|
||||
|
||||
Reference in New Issue
Block a user