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spostato appunti neuron

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# **Presynaptic Release Model: Sequence of Events & Multi-Timescale Modulations**
## **CORE RELEASE SEQUENCE (Milliseconds)**
### **Event 1: Action Potential Arrival**
```
Time: t = 0 ms
Trigger: Depolarization from axon hillock
Mechanism: Na⁺/K⁺ voltage-gated channel cascade
State: Terminal depolarizes from -70 mV to +30 mV
Duration: ~1 ms
```
### **Event 2: VGCC Opening**
```
Time: t = 0.2-0.5 ms after AP arrival
Trigger: Membrane depolarization > -40 mV
Types: CaV2.1 (P/Q-type), CaV2.2 (N-type) at active zone
Mechanism: Voltage sensor movement → pore opening
Open probability: ~0.3-0.8 during AP peak
Open duration: ~0.5-2 ms
```
### **Event 3: Ca²⁺ Influx & Microdomain Formation**
```
Time: t = 0.3-1 ms after AP arrival
Ca²⁺ source: Extracellular (1.2 mM) → intracellular (50 nM baseline)
Influx rate: ~3000-10000 Ca²⁺ ions per VGCC per ms
Microdomain formation:
- Within 20 nm of VGCC: 10-100 µM
- At vesicle release site: 10-25 µM threshold for release
- Rise time: <100 µs
- Diffusion-limited spread: ~100-200 nm radius
```
### **Event 4: Vesicle Release Decision**
```
Time: t = 0.4-1.5 ms after AP arrival
Decision conditions (AND logic):
1. [Ca²⁺]microdomain > 10-25 µM
2. Vesicle in RRP (docked & primed)
3. SNARE complex in primed state
4. Synaptotagmin Ca²⁺ binding sites occupied
Mechanism:
- Ca²⁺ binds synaptotagmin (4+ cooperative sites)
- Synaptotagmin displaces complexin clamp
- SNARE complex completes zippering
- Vesicle membrane fuses with presynaptic membrane
Release latency: 0.1-1.0 ms after Ca²⁺ threshold reached
Release synchrony: Multiple vesicles can release simultaneously
```
### **Event 5: Ca²⁺ Clearance**
```
Time: t = 1-50 ms after influx
Clearance mechanisms (in order of speed):
1. Fast buffers (calbindin, parvalbumin): <1 ms
2. Plasma membrane Ca²⁺ ATPase (PMCA): 10-100 ms
3. Na⁺/Ca²⁺ exchanger (NCX): 10-100 ms
4. Mitochondrial uptake: 10-1000 ms
5. Endoplasmic reticulum uptake: 100-1000 ms
Residual Ca²⁺: 0.1-0.5 µM persists for 10-1000 ms
```
### **Event 6: Vesicle Recycling**
```
Time: t = 10 ms - 10 s (depending on activity)
Sequential steps:
1. Endocytosis (clathrin-mediated, kiss-and-run, bulk)
2. Vesicle re-acidification (v-ATPase)
3. Neurotransmitter reloading (vesicular transporters)
4. Priming (SNARE assembly, docking)
5. Return to RRP
Recycling rate: Limited by ATP availability
```
## **MODULATION MATRIX ACROSS TIMESCALES**
### **MODULATION LEVEL 1: MILLISECONDS (Immediate Signal Processing)**
| Event | Modulator | Effect | Mechanism | Timescale |
|------------------|-----------------------------------|----------------------------------------|---------------------------------------------|---------------------|
| **VGCC Opening** | Voltage waveform | AP width/duration affects open time | K⁺ channel activation shapes repolarization | During AP (1 ms) |
| **VGCC Opening** | Ca²⁺-dependent inactivation (CDI) | Auto-inhibition | Ca²⁺ binding to calmodulin on VGCC | 5-50 ms |
| **Ca²⁺ Microdomain** | Endogenous buffers | Shapes [Ca²⁺] spatial/temporal profile | Calbindin, parvalbumin binding | <1 ms |
| **Release Decision** | Synaptotagmin isoforms | Different Ca²⁺ sensitivity | Cooperative binding sites vary | During Ca²⁺ binding |
| **Release Decision** | SNARE complex state | Priming level determines speed | Munc13 activity, NSF disassembly | <1 ms |
| **Ca²⁺ Clearance** | Fast buffers | Immediate Ca²⁺ binding | High-affinity Ca²⁺ binding proteins | <1 ms |
### **MODULATION LEVEL 2: TENS-HUNDREDS OF MILLISECONDS (Short-term Plasticity)**
| Event | Modulator | Effect | Mechanism | Timescale |
|---------------------|----------------------|-------------------------------|-----------------------------------------------------|---------------|
| **VGCC Opening** | Residual Ca²⁺ | Ca²⁺-dependent facilitation | Ca²⁺/CaM binding to VGCC β-subunit | 10-1000 ms |
| **VGCC Opening** | eCB (CB1 activation) | Direct inhibition | Gβγ subunit blocks pore | 100-2000 ms |
| **Ca²⁺ Microdomain** | Mitochondrial uptake | Buffer capacity changes | Uniporter activity with Ca²⁺ buildup | 10-1000 ms |
| **RRP Replenishment** | Residual Ca²⁺ | Enhanced mobilization | Calcineurin activation → synapsin dephosphorylation | 10-1000 ms |
| **RRP Replenishment** | ATP availability | Limits priming rate | NSF, v-ATPase, priming ATPases | Continuous |
| **Release Probability** | mGluR autoreceptors | Activity-dependent inhibition | Gi/o → ↓cAMP → ↓PKA → ↓VGCC | 50-500 ms |
| **Ca²⁺ Clearance** | PMCA/NCX pumps | Activity-dependent saturation | Limited pump capacity during high frequency | 10-1000 ms |
| **Vesicle Recycling** | Activity level | Different endocytosis modes | High activity → bulk endocytosis | 100 ms - 10 s |
### **MODULATION LEVEL 3: SECONDS-MINUTES (Metabolic & Signaling)**
| Event | Modulator | Effect | Mechanism | Timescale |
|-------------------|-----------------------------|----------------------------|-----------------------------------------|--------------|
| **VGCC Density** | Surface expression | More/fewer channels | Phosphorylation-dependent trafficking | 30 s - 5 min |
| **VGCC Function** | Kinase phosphorylation | Changed open probability | PKA, PKC, CaMKII phosphorylation | 1-10 min |
| **Ca²⁺ Dynamics** | NO (cGMP pathway) | Altered pump activity | PKG phosphorylation of PMCA | 1-10 min |
| **Vesicle Pools** | Mobilization rate | RP→RRP speed changes | Synapsin phosphorylation state | 1-10 min |
| **ATP Production** | Lactate shuttle | Enhanced ATP supply | Astrocyte-neuron metabolic coupling | 1-10 min |
| **Release Machinery** | BDNF (acute) | Enhanced priming & docking | TrkB → PLCγ → PKC activation | 1-10 min |
| **Autoreceptor** | mGluR desensitization | Reduced autoinhibition | β-arrestin recruitment, internalization | 1-10 min |
| **CB1 Receptor** | eCB-induced desensitization | Reduced inhibition | GRK phosphorylation, internalization | 1-10 min |
| **Ca²⁺ Clearance** | Mitochondrial adaptation | Increased capacity | Matrix Ca²⁺ activates dehydrogenases | 1-10 min |
### **MODULATION LEVEL 4: MINUTES-HOURS (Structural & Transcriptional)**
| Event | Modulator | Effect | Mechanism | Timescale |
|-----------------------|--------------------|-------------------------------|----------------------------------------------|---------------|
| **VGCC Expression** | BDNF (chronic) | Increased channel synthesis | TrkB → MAPK → CREB → gene expression | 30 min - 6 hr |
| **VGCC Expression** | Activity-dependent | Homeostatic scaling | Ca²⁺ → NFAT/CREB → VGCC genes | 1-24 hr |
| **Active Zone Size** | BDNF, activity | More release sites | Structural proteins (RIM, Bassoon) synthesis | 1-12 hr |
| **Vesicle Pool Size** | BDNF, activity | Larger RP/RRP | Synaptic vesicle protein synthesis | 1-12 hr |
| **SNARE Machinery** | Local translation | More fusion complexes | mTOR-dependent protein synthesis | 30 min - 3 hr |
| **Mitochondrial Density** | BDNF, activity | Increased ATP capacity | PGC-1α activation → biogenesis | 3-24 hr |
| **Metabolic Pathways** | Activity patterns | Enhanced glycolysis/oxidation | HIF-1α, AMPK pathway activation | 1-6 hr |
| **Receptor Expression** | Chronic modulation | mGluR, CB1 level changes | Transcriptional regulation | 3-12 hr |
| **Buffer Expression** | Ca²⁺ history | Calbindin/parvalbumin levels | Ca²⁺-dependent gene regulation | 3-12 hr |
### **MODULATION LEVEL 5: HOURS-DAYS (Metaplasticity & Structural Remodeling)**
| Event | Modulator | Effect | Mechanism | Timescale |
|---------------------------|-----------------------|-------------------------------------|--------------------------------------------|-----------|
| **Synapse Size** | Chronic activity | Growth/shrinkage | Cytoskeletal reorganization | 6-48 hr |
| **VGCC Distribution** | Activity patterns | Clustering changes | Scaffold protein (Homer, Shank) expression | 12-72 hr |
| **Release Site Organization** | BDNF, activity | Active zone architecture | Piccolo, Bassoon, RIM expression | 12-72 hr |
| **Vesicle Recycling** | Chronic patterns | Efficiency changes | Endocytosis machinery expression | 12-48 hr |
| **Metaplasticity Rules** | Activity history | Altered LTP/LTD thresholds | Kinase/phosphatase expression changes | 24-72 hr |
| **Energy Allocation** | Chronic demand | Mitochondrial positioning | Motor protein (kinesin, dynein) adaptation | 12-48 hr |
| **Network Integration** | System-level activity | Presynaptic inhibition/facilitation | Interneuron connectivity changes | 24-96 hr |
## **MODULATION CASCADES (How Signals Propagate Through Events)**
### **Example 1: High-Frequency Activity Cascade**
```
Event Timeline:
t = 0 ms: First AP → Release (high Pr)
t = 10 ms: Second AP → Enhanced release (residual Ca²⁺ facilitation)
t = 100 ms: Tenth AP → Depressed release (RRP depletion, eCB inhibition)
Modulation Cascade:
Milliseconds: CDI develops, buffers saturate
Seconds: mGluR autoinhibition builds, ATP depletes
Minutes: BDNF synthesis begins, pumps adapt
Hours: VGCC expression increases, active zone grows
Days: Synapse strengthens, metaplasticity changes
```
### **Example 2: BDNF-Mediated Potentiation Cascade**
```
Event Timeline:
t = 0-5 min: BDNF binds TrkB receptors
t = 5-30 min: Kinase cascades activate
t = 30-120 min: Local protein synthesis
t = 3-24 hr: Structural changes
Modulation Cascade:
Milliseconds: Immediate VGCC phosphorylation (↑ open probability)
Seconds: Enhanced vesicle priming (↑ RRP replenishment)
Minutes: More SNARE complexes synthesized (↑ release sites)
Hours: Additional VGCCs inserted (↑ Ca²⁺ influx capacity)
Days: Active zone expansion (↑ number of release sites)
```
### **Example 3: eCB-Mediated Depression Cascade**
```
Event Timeline:
t = 100 ms: eCB produced postsynaptically
t = 200 ms: CB1 activation inhibits VGCCs
t = 1-10 min: β-arrestin recruitment, CB1 internalization
t = 1-24 hr: CB1 downregulation, structural changes
Modulation Cascade:
Milliseconds: Direct VGCC block (↓ Ca²⁺ influx)
Seconds: Reduced cAMP → ↓ PKA → ↓ vesicle priming
Minutes: CB1 internalization → reduced inhibition
Hours: CB1 downregulation → reduced modulatory capacity
Days: Synaptic downscaling → smaller active zone
```
## **CROSS-EVENT MODULATION PATTERNS**
### **Feedforward Loops:**
```
Positive:
AP → Ca²⁺ influx → CaMKII activation → ↑ VGCC phosphorylation → ↑ Ca²⁺ influx
Negative:
AP → Glutamate release → mGluR activation → ↓ VGCC opening → ↓ Ca²⁺ influx
```
### **Feedback Loops:**
```
Homeostatic:
High activity → Ca²⁺ buildup → gene expression → more buffers/pumps → ↓ Ca²⁺ buildup
Trophic:
Activity → BDNF release → structural growth → more release sites → more activity
```
### **Energy Management Loops:**
```
Energy Conservation:
ATP depletion → AMPK activation → ↓ protein synthesis → ↓ energy consumption
Energy Investment:
BDNF + adequate ATP → mTOR activation → protein synthesis → structural growth
```
## **INTEGRATED TIMELINE OF A RELEASE EVENT WITH MODULATIONS**
### **t = 0-1 ms (AP to Release)**
```
Primary events: AP → VGCC open → Ca²⁺ influx → Release
Modulations active:
- AP shape from previous activity (K⁺ channel adaptation)
- VGCDI from recent Ca²⁺ history
- SNARE priming from recent ATP availability
- Buffer capacity from expression levels
```
### **t = 1-100 ms (Immediate Aftermath)**
```
Primary events: Ca²⁺ clearance, vesicle recycling initiation
Modulations active:
- Residual Ca²⁺ facilitating next release
- mGluR autoinhibition building
- eCB production if postsynaptic Ca²⁺ high
- ATP consumption for pumps and recycling
```
### **t = 100 ms - 1 min (Short-term Adaptation)**
```
Primary events: RRP replenishment, metabolic adjustments
Modulations active:
- Kinase/phosphatase balance shifting
- NO production if sustained activity
- BDNF release if activity pattern significant
- Mitochondrial Ca²⁺ uptake affecting ATP
```
### **t = 1 min - 1 hr (Medium-term Plasticity)**
```
Primary events: Protein synthesis, trafficking changes
Modulations active:
- Local translation of VGCCs, SNAREs
- Receptor trafficking to/from surface
- Mitochondrial positioning changes
- Metabolic pathway adjustments
```
### **t = 1 hr - days (Long-term Restructuring)**
```
Primary events: Structural changes, gene expression
Modulations active:
- Nuclear signaling for gene expression
- Cytoskeletal reorganization
- Synapse growth/shrinkage
- Metaplasticity rule changes
```
## **MODELING PRINCIPLES**
1. **Hierarchical Modulation**: Faster events constrain slower adaptations
2. **Bidirectional Coupling**: Every modulation affects and is affected by release events
3. **Energy Constraints**: ATP availability gates all processes
4. **History Dependence**: Past activity patterns determine current modulation states
5. **Context Specificity**: Same modulator can have opposite effects depending on timing/context
6. **Redundancy**: Multiple pathways can achieve similar outcomes
7. **Trade-offs**: Every enhancement has costs (energy, stability, flexibility)
This model shows how a simple millisecond release event sits at the center of a rich, multi-timescale regulatory network where each release both responds to and influences modulations across seconds to days, creating a dynamic, self-tuning system for synaptic transmission.