Synapse

... the molecular structure and function of a neuronal synapse is one of the most complex and beautiful biological systems we know.Let’s go step-by-step from the molecular architecture of the pre- and postsynaptic compartments to the signal transduction events that underlie neural communication.

1. Synapse Overview

A synapse is the molecular interface between two neurons (or a neuron and a muscle/gland).It consists of:

1. Presynaptic terminal (axon bouton): where neurotransmitters are released.

2. Synaptic cleft (~20–40 nm): extracellular gap containing adhesion and scaffold molecules.

3. Postsynaptic density (PSD): receptor-rich zone on the receiving neuron’s dendritic spine or soma.

⚡ 2. Presynaptic Molecular Machinery

a. Synaptic Vesicle Cycle

Synaptic vesicles (~40 nm) store neurotransmitters like glutamate, GABA, acetylcholine, or dopamine.

Main steps and molecules:

1. Vesicle Loading

   • Neurotransmitters are pumped into vesicles via V-ATPase (proton pump creating ΔpH) and antiporters:

     • VGLUTs (glutamate transporters)

     • VGAT (GABA/glycine)

     • VAChT (acetylcholine)

     • VMAT (monoamines)

2. Docking and Priming

   • Vesicles are tethered near the active zone by Rab3A, RIM, Munc13, and SNARE proteins.

   • The SNARE complex (core fusion machine) consists of:

     • Synaptobrevin/VAMP (vesicle membrane)

     • Syntaxin-1 (plasma membrane)

     • SNAP-25 (plasma membrane)

   • Munc18 regulates SNARE assembly into a tight four-helix bundle (energy stored for fusion).

3. Calcium Triggering

   • An arriving action potential opens voltage-gated Ca²⁺ channels (Cav2.1 / Cav2.2).

   • Ca²⁺ binds synaptotagmin (the Ca²⁺ sensor), which interacts with the SNARE complex and phospholipids.

   • This binding induces membrane fusion within microseconds.

4. Fusion and Release

   • Lipid bilayers merge → neurotransmitter is released by exocytosis into the synaptic cleft.

5. Endocytosis and Recycling

   • After release, vesicle membrane is retrieved by clathrin-mediated endocytosis or kiss-and-run mechanisms.

   • Proteins: Clathrin, AP2, dynamin, amphiphysin, synaptojanin.

   • Vesicles are refilled and re-enter the cycle.

3. The Synaptic Cleft (Nano-architecture)

The cleft (~20 nm wide) contains cell adhesion and organizing molecules ensuring alignment:

• Neurexins (presynaptic) bind neuroligins (postsynaptic).

• SynCAMs, cadherins, and integrins stabilize contact.

• Extracellular matrix components (e.g., tenascin-R, laminins) influence synaptic plasticity.

These interactions ensure precise pre- and postsynaptic alignment at the nanometer scale.

4. Postsynaptic Molecular System

a. Neurotransmitter Receptors

Receptors determine the electrical or biochemical response.They are classified into:

1. Ionotropic receptors (ligand-gated ion channels)

Fast synaptic transmission:

• Glutamate: AMPA (GluA1-4), NMDA (GluN1-3), kainate receptors.

• GABA: GABA_A receptors (Cl⁻ channel).

• Glycine: GlyR (Cl⁻).

• Acetylcholine: nicotinic AChR (Na⁺/K⁺ channel).

2. Metabotropic receptors (GPCRs)

Slow modulatory signaling:

• mGluRs, GABA_B, dopamine (D1–D5), serotonin (5-HT), muscarinic AChRs.

• Coupled to G-proteins (Gα, Gβγ) → second messengers (cAMP, DAG, IP₃, Ca²⁺).

b. Postsynaptic Density (PSD) — Molecular Scaffolding

The PSD is a dense protein network (~300–500 nm wide) beneath the postsynaptic membrane, crucial for receptor clustering and signal integration.

Main molecular families:

• PSD-95 (DLG4), SAP97, GKAP, SHANK, Homer — scaffold proteins.

• Actin cytoskeleton regulates spine morphology and receptor mobility.

• CaMKII, PKC, PP1/2A, Src kinases — phosphorylation control plasticity.

Example:

• NMDA receptor activation → Ca²⁺ influx → CaMKII activation → AMPA receptor insertion (LTP mechanism).

5. Synaptic Plasticity (Molecular Learning)

Synapses dynamically change strength — the basis of memory.

Long-Term Potentiation (LTP)

• High-frequency stimulation → NMDA receptor opens → Ca²⁺ influx.

• Ca²⁺ activates CaMKII, PKA, and CREB → enhances AMPA receptor insertion and gene transcription.

Long-Term Depression (LTD)

• Moderate Ca²⁺ → calcineurin (phosphatase) → AMPA receptor internalization.

Protein synthesis & transport

• Local translation of mRNAs near spines (via FMRP, RNA granules) sustains long-term structural changes.

⚙️ 6. Energy and Homeostasis

• Mitochondria near active zones supply ATP for vesicle priming and Ca²⁺ buffering.

• Na⁺/K⁺-ATPase restores membrane potential post-spike.

• Endoplasmic reticulum and SERCA pumps regulate local Ca²⁺ stores.

7. Molecular Schematic Summary

[Action Potential]
    ↓
Voltage-gated Ca2+ channels open
    ↓
Ca2+ binds Synaptotagmin → SNARE fusion → Neurotransmitter release
    ↓
Neurotransmitter binds receptors on postsynaptic membrane
    ↓
Ion flux or GPCR signaling → EPSP / IPSP
    ↓
Receptor modulation (LTP/LTD)
    ↓
Plasticity → Memory encoding

8. When Synaptic Molecules Fail

Dysfunction	Molecular Defect	Result
Botulinum / Tetanus toxin	Cleave SNARE proteins	Block neurotransmitter release
Schizophrenia, Autism	Mutations in neurexin/neuroligin, SHANK3	Altered synaptic connectivity
Alzheimer’s disease	Aβ oligomers disrupt NMDA signaling and PSD integrity	Synaptic loss
Epilepsy	GABA_A receptor or ion channel mutations	Hyperexcitability
Parkinson’s	Loss of dopaminergic terminals; α-synuclein aggregation	Reduced vesicle recycling