- 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.
- 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.
- **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)
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.
Serve a dare la velocita' al trasporto di vesicles da RP a RRP. 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 Tr_Ca 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.
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
```Gen
interacting: RPShuttleLow
contained_by: PRESYNAPSE
in_context: NOT AP_ctx
rf: ( active: 48x ) # Low
hypothesis: (CaTrace emptiness) OR
(RP emptiness) OR
(RRP fullness)
action: [RP decrease, RRP increase]
trace: None
```
##### RPShuttleMedium: interacting
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
```Gen
interacting: RPShuttleMedium
contained_by: PRESYNAPSE
in_context: AP_ctx
rf: ( active: 24x ) # Medium
hypothesis: (CaTrace mediumness) AND (RP mediumness) AND (RRP mediumness) OR
(CaTrace fullness) AND (RP mediumness) AND (RRP mediumness) OR # signal boost
(CaTrace mediumness) AND (RP fullness) AND (RRP mediumness) OR # supply boost
(CaTrace mediumness) AND (RP mediumness) AND (RRP emptiness) # vacancy boost
action: [RP decrease, RRP increase]
trace: None
```
##### RPShuttleHigh: interacting
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
```Gen
interacting: RPShuttleHigh
contained_by: PRESYNAPSE
in_context: AP_ctx
rf: ( active: 12x ) # Fast
hypothesis: (CaTrace fullness) AND (RP fullness) AND (RRP mediumness) OR # signal + supply
(CaTrace fullness) AND (RP mediumness) AND (RRP emptiness) OR # signal + vacancy
(CaTrace mediumness) AND (RP fullness) AND (RRP emptiness) # supply + vacancy
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:
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.
#### VGCC-PRE-TUN: Tuner
```Gen
tuner: VGCC-PRE-TUN
contained_by: PRESYNAPSE
tunes: PRESYNAPSE/expansion/PRESYNAPSE-VCGG
tub_modulation: # in TUN agiamo su POS/ACT
- posMod ( fullness: None, active: PRESYNAPSE-VCGG/fullness, empty: 0x) # riferimento a possible di PRESYNAPSE-VCGG
- actMod ( fullness: None, active: PRESYNAPSE-VCGG/active, empty: PRESYNAPSE-VCGG/emptiness) # riferimento a active di PRESYNAPSE-VCGG
# qui stiamo modulando possible e actual di PRESYNAPSE-VCGG associandoli
# a posMod e actMod. Non serve associare una fullness perche'
# la modulazione e' una pompa fra posMod e actMod e controlliamo
Voltage-Controlled Gated Channels: Qui per ora non gestiamo l'evoluzione della depolarizzazione. Alla scomparsa dell'AP, i VGCC smettono di funzionare.
-- 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 eliminiamo Ca2+. 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 anche in bae alle tracce di Ca2+ che prendiamo in presynapse.
