Synaptic vesicles containing neurotransmitter

Active zone for docking and fusion

Voltage-gated Ca²⁺ channels

Mitochondria for energy supply

Narrow extracellular gap (~20–40 nm in many chemical synapses)

Extracellular matrix and enzymes that can degrade transmitter

Neurotransmitter receptors (ionotropic, metabotropic)

Postsynaptic density (scaffold proteins organizing receptors and signaling molecules)

Ion channels and signaling pathways

Astrocytes (tripartite synapse concept)

Microglia

Neurotransmitter release from vesicles

Typically unidirectional (pre → post)

Slower than electrical but highly modulable and diverse

Direct ionic current flow via gap junctions (connexons)

Often bidirectional

Very fast, supports synchronization

Combine electrical coupling and chemical transmitter release

Depolarization invades axon terminal membrane

Ca²⁺ influx down electrochemical gradient

Local Ca²⁺ microdomains near active zones

Vesicles positioned for fast release at the active zone

SNARE complex assembly (fusion machinery)

Ca²⁺ binds sensor proteins (e.g., synaptotagmin)

Vesicle membrane fuses with presynaptic membrane

Neurotransmitter released in quanta

Transmitter crosses cleft rapidly (µs–ms)

Binds clustered postsynaptic receptors

Ionotropic receptors

Metabotropic receptors

Presynaptic reuptake (e.g., DAT, SERT, NET)

Glial uptake (e.g., glutamate EAATs)

Enzymatic degradation (e.g., AChE for acetylcholine)

Diffusion/spillover away from synapse

Endocytosis retrieves membrane

Vesicles refilled via vesicular transporters

Returned to releasable pools

Ions and small molecules pass directly

Minimal synaptic delay (near-instant)

Can filter signals (passes subthreshold potentials)

Supports synchronization and oscillations

Depolarizes postsynaptic membrane

Increases action potential probability

Common transmitter: glutamate (CNS)

Typical receptors

Hyperpolarizes or stabilizes membrane potential

Decreases firing probability

Common transmitters: GABA (brain), glycine (spinal cord/brainstem)

Typical receptors

Adjusts excitability, synaptic strength, network dynamics

Often metabotropic and diffuse projections

Key modulators: dopamine, serotonin, norepinephrine, acetylcholine, histamine

Typically ~1–5 ms (Ca²⁺ entry, fusion, diffusion, receptor activation)

Temporal summation (inputs close in time add)

Spatial summation (inputs from multiple synapses add across dendrites/soma)

Facilitation (residual presynaptic Ca²⁺ raises release probability)

Depression (vesicle depletion or receptor desensitization)

Post-tetanic potentiation (longer enhancement after high-frequency activity)

Dendrites: many synapses, local nonlinear processing

Soma/axon initial segment: action potential initiation zone

EPSP/IPSP sign depends on ion gradients and receptor conductances

Shunting inhibition

NMDA spikes, dendritic spikes, compartmentalized signaling

Persistent strengthening after specific activity patterns

Often NMDA-dependent Ca²⁺ influx

Increased AMPA insertion and/or presynaptic release probability

Persistent weakening

Different Ca²⁺ regimes and phosphatase activity

Spine size/number changes; synapse formation/elimination

Maintains overall activity levels (synaptic scaling)

Glutamate, GABA, glycine, acetylcholine

Monoamines: dopamine, serotonin, norepinephrine

Neuropeptides: substance P, endorphins (often modulatory, longer-lasting)

Ionotropic: AMPA, NMDA, kainate, GABA_A, nicotinic ACh

Metabotropic: mGluRs, GABA_B, muscarinic ACh, dopamine receptors

SNAREs (synaptobrevin/VAMP, syntaxin, SNAP-25)

Synaptotagmin (Ca²⁺ sensor)

Transporters (DAT, SERT, NET; EAATs)

Enzymes (AChE; MAO/COMT in monoamine metabolism pathways)

Autoreceptors regulate release (feedback)

Ca²⁺ channel modulation changes release probability

Readily releasable pool size affects efficacy

Receptor trafficking/phosphorylation alters number and sensitivity

Receptor desensitization

Spine morphology and scaffolding changes

Astrocyte gliotransmitters (context-dependent)

Uptake shapes spillover and timing

SSRIs block reuptake → increase synaptic serotonin

Cocaine blocks monoamine reuptake (DAT/NET/SERT)

Benzodiazepines enhance GABA_A receptor function

NMDA antagonists alter excitation (e.g., anesthetics, ketamine)

Botulinum toxin disrupts SNAREs → blocks ACh release → paralysis

Tetanus toxin blocks inhibitory transmitter release → spastic paralysis

Myasthenia gravis: antibodies against nicotinic ACh receptors

Epilepsy: excitation/inhibition imbalance

Parkinson’s disease: dopamine depletion affects synaptic modulation