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presynapse.md
- qui comprendiamo: PRESYNASPE
PRESYNAPSE
Intro:
- is expanded and developed by: AXON
- is tuned by: ORGANISM, organs, modules
- expands and tunes: PRE_VGG
- develops _Ca2, _Rrp
PRESYNAPSE
type: comprehension
include: pre_vgcc.md
expansion:
_@pre_vgcc: TUB [ comprehension: PRE_VGCC, full: 10x, active: 5x, empty: 2x ]
# il tub serve al tuning
intrication:
# Scope
!DAY: INTRICATION [ ref: &ORGANISM.!DAY ]
!NIGHT: INTRICATION [ ref: &ORGANISM.!NIGHT ]
# Context
*AP: INTRICATION [ ref: &SOMA.*AP ]
*TunePossible: INTRICATION [ ref: &... ] # To be defined...
# Tub
_NT: INTRICATION [ ref: &ASTROSYNAPSE._NT ]
_ATP: INTRICATION [ ref: &ASTROCYTE._ATP ]
_eCB: INTRICATION [ ref: &POSTSYNAPSE._eCB ]
instantiation:
# Context
*VcggPreActiveIncrease: CONTEXT []
*VcggPreActiveDecrease: CONTEXT []
*Ca2PrePreActiveDecrease: CONTEXT []
*Ca2PreActiveDecrease: CONTEXT []
*RrpPreActiveDecrease: CONTEXT []
*RrpPreActiveDecrease: CONTEXT []
# Tub
_Ca2: TUB [ full: 60x, active: 30x, empty: 0x ]
_Rrp: TUB [ full: 30x, active: 15x, empty: 0x ]
_Rp: TUB [ full: 30x, active: 15x, empty: 0x ]
_CaTracesHigh: TUB [ full: 50x, active: 0x, empty: 0x ]
_CaTracesMedium: TUB [ full: 50x, active: 0x, empty: 0x ]
_CaTracesLow: TUB [ full: 50x, active: 0x, empty: 0x ]
_Ca2FullDev: TUB [ full: 100x, active: _Ca2.full, empty: 40x ]
_RrpFullDev: TUB [ full: 100x, active: _Rrp.full, empty: 40x ]
# serve al DEV
# Behaviour
$: BEHAVIOUR [ behaviour: MAIN_PRE ]
$: BEHAVIOUR [ behaviour: TUNE_PRE_VGCC ]
$: BEHAVIOUR [ behaviour: DEV_PRE_TUBS ]
MAIN_PRE: !DAY
MAIN_PRE
type: behaviour
within_scope: !DAY
snippet:
# *AP
@: ACCUMULATOR [ snippet: NTreleaseLow, rf: active 12x ]
@: ACCUMULATOR [ snippet: NTreleaseMedium, rf: active 9x ]
@: ACCUMULATOR [ snippet: NTreleaseHigh, rf: active 6x ]
@: ACCUMULATOR [ snippet: TracesAccLow, rf: active 3x ]
@: ACCUMULATOR [ snippet: TracesAccMedium, rf: active 6x ]
@: ACCUMULATOR [ snippet: TracesAccHigh, rf: active 10x ]
# NOT *AP
@: ACCUMULATOR [ snippet: eCBClearenceMedium, rf: active 24x ]
@: ACCUMULATOR [ snippet: eCBClearenceLow, rf: active 48x ]
@: ACCUMULATOR [ snippet: RPShuttleLow, rf: active 24x ]
@: ACCUMULATOR [ snippet: RPShuttleMedium, rf: active 48x ]
@: ACCUMULATOR [ snippet: RefillGlutamine, rf: active 24x ]
@: ACCUMULATOR [ snippet: TracesClearance, rf: active 30x ]
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
- _CaTracesXXX: sono le tracce di permanenza della concentrazione di Ca2. Servono alla modulazione (TUN)
- _eCB: retrograde signal updates from postsynapsis (postsynaptic input)
*AP
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
NTreleaseLow
NTreleaseLow
type: accumulator
in_context: *AP
hypothesis: _Ca2 mediumness AND _Rrp mediumness AND NOT _ATP empty
action: [ _Rrp decrease, _NT increase, _ATP decrease ]
trace: None
NTreleaseMedium
NTreleaseMedium
type: accumulator
in_context: *AP
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
NTreleaseHigh
type: accumulator
in_context: *AP
hypothesis: _Ca2 fullness AND _Rrp fullness AND
NOT _ATP empty
action: [ _Rrp decrease, NT increase, _ATP decrease ]
trace: None
Ca2TracesAccLow
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, *TunePossible
- 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 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.
Ca2TracesAccuLow
type: accumulator
in_context: *AP
hypothesis: _Ca2 emptiness
action: [ _CaTraceLow increase ]
trace: None
Ca2TracesAccMedium
Ca2TracesAccMedium
type: accumulator
in_context: *AP
hypothesis: _Ca2 mediumness
action: [ _CaTraceMed increase ]
trace: None
Ca2TracesAccHigh
Ca2TracesAccumulationHigh
type: accumulator
in_context: *AP
hypothesis: _Ca2 fullness
action: [ _CaTraceHigh increase ]
trace: None
NOT *AP
eCBClearance
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.
eCBClearance: ( active: 24x ) # Slow
type: accumulator
in_context: NOT *AP
hypothesis: NOT _eCB empty
action: [ _eCB decrease ]
trace: None
RPShuttleLow
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
RPShuttleLow
type: accumulator
in_context: NOT *AP
hypothesis: _CaTraceLow fullness OR
_RP emptiness OR
_Rrp fullness
action: [ _RP decrease, _Rrp increase ]
trace: None
RPShuttleMedium
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
RPShuttleMedium
type: accumulator
in_context: *AP
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
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
RPShuttleHigh
type: accumulator
in_context: *AP
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
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.
Ca2TracesClearance
Qui facciamo un flush di CaTraceX. Deve essere fatto a valle del tuning.
Ca2TracesClearance
type: accumulator
in_context: NOT *TunePossible
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
TUNE_PRE_VGCC: !DAY
TUNE_PRE_VGCC
type: behaviour
# qui stiamo aggiungendo o eliminando PRE_VGCC. Fra un massimo full e minimo empty (empty puo' non essere 0)
# contained_by: PRESYNAPSE non e' contenuto, si attacca.
activity_scope: !DAY
snippet:
# *TunePossible
@: CONTEXTOR [ snippet: VgccPreTunCheck, rf: active 60x ]
# *VcggPreActiveIncrease
@: ACCUMULATOR [ snippet: VcggPreActiveIncrease, rf:active 10x ]
# *VcggPreActiveDecrease
@: ACCUMULATOR [ snippet: VcggPreActiveDecrease, rf:active 10x ]
*TunePossible
VgccPreTunCheck
Qui controlliamo che ci siano le condizioni per aumentare o diminuire la quantita' di VGCC
VgccPreTunCheck
type contextor
in_context: *TunePossible
condition: _CaTraceHigh fullness
out_context: *VcggPreActiveIncrease
condition: _CaTraceLow fullness
out_context: *VcggPreActiveDecrease
*VcggPreActiveIncrease
VcggPreActiveIncrease
VcggPreActiveIncrease
type: accumulator
in_context: *VcggPreActiveIncrease
hypothesis:
action:
trace:
*VcggPreActiveDecrease
VcggPreActiveDecrease
VcggPreActiveDecrease
type: accumulator
in_context: *VcggPreActiveDecrease
hypothesis:
action:
trace:
DEV_PRE_TUBS: !NIGHT
DEV_PRE_TUBS
type: behaviour
activity_scope: !NIGHT
snippet:
# *fixed
@: CONTEXTOR [ snippet: Ca2PreDevCheck, rf: active 60x ]
*Ca2PreFullDecrease
@: ACCUMULATOR [ snippet: Ca2PreFullDecrease, rf: active 10x ]
*Ca2PreFullIncrease
@: ACCUMULATOR [ snippet: Ca2PreFullIncrease, rf: active 10x ]
# *fixed
@: CONTEXTOR [ snippet: RrpPreDevCheck, rf: active 60x ]
*RrpPreFullDecrease
@: ACCUMULATOR [ snippet: RrpPreFullDecrease, rf: active 10x ]
*IncreaseRrpFull
@: ACCUMULATOR [ snippet: IncreaseRrpFull, rf: active 10x ]
*fixed
Ca2PreDevCheck
Tens Milliseconds Time Scale
Ca2PreDevCheck
type: contextor
in_context: *fixed
condition: ( empty )
out_context: *Ca2PreFullDecrease
condition: ( full)
out_context: *Ca2PreFullIncrease
*Ca2PreFullDecrease
Ca2PreFullDecrease
DecreasePreCa2Full
type: accumulator
in_context: *Ca2PreFullDecrease
hypothesis: NOT ( full ) AND NOT ( empty )
action: [ increase, decrease]
trace: None
*Ca2PreFullIncrease
Ca2PreFullIncrease
IncreasePreCa2Full
type: accumulator
in_context: *Ca2PreFullIncrease
hypothesis: NOT ( full ) AND NOT ( empty )
action: [ increase, decrease]
trace: None
*fixed
RrpPreDevCheck
Tens Milliseconds Time Scale
RrpPreDevCheck
type: contextor
in_context: *fixed
condition: ( empty )
out_context: *RrpPreFullDecrease
condition: ( full)
out_context: *IncreaseRrpFull
*RrpPreFullDecrease
RrpPreFullDecrease
DecreasePreRrpFull
type: accumulator
in_context: *RrpPreFullDecrease
hypothesis: NOT ( full ) AND NOT ( empty )
action: [ increase, decrease]
trace: None
*RrpPreFullIncrease
RrpPreFullIncrease
RrpPreFullIncrease
type: accumulator
in_context: *RrpPreFullIncrease
hypothesis: NOT ( full ) AND NOT ( empty )
action: [ increase, decrease]
trace: None