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synaptic vesicle

Neuroscience / PhysiologyNervous systemNeuromuscular junctionCentral nervous systemPeripheral nervous system

Summary

Synaptic vesicles are small (~40-50 nm) membrane-bound organelles in presynaptic terminals that store and release neurotransmitters by Ca2+-triggered exocytosis. Their fusion with the presynaptic membrane is mediated by SNARE proteins and is the target of botulinum and tetanus toxins.

Detail

STRUCTURE AND CONTENTS: Synaptic vesicles are ~40-50 nm lipid-bilayer vesicles concentrated in the presynaptic axon terminal. They are filled with neurotransmitter (ACh, glutamate, GABA, glycine, monoamines) by vesicular transporters (e.g., VMAT for monoamines, VAChT for ACh, VGLUT for glutamate). Loading is driven by a proton gradient generated by a V-type H+-ATPase. Large dense-core vesicles store neuropeptides and are made in the soma, then transported down the axon.

VESICLE CYCLE: (1) Filling with neurotransmitter. (2) Docking at the active zone. (3) Priming. (4) Ca2+-triggered fusion and exocytosis. (5) Endocytic recycling, which is clathrin- and dynamin-mediated. Vesicles are then refilled.

KEY PROTEINS: - v-SNAREs: synaptobrevin (VAMP) on the vesicle. - t-SNAREs: syntaxin and SNAP-25 on the target (plasma) membrane. Together they form the SNARE complex that drives membrane fusion. - Synaptotagmin: the Ca2+ sensor on the vesicle. Ca2+ entry through voltage-gated Ca2+ channels triggers fusion. - Synapsin: tethers vesicles to the actin cytoskeleton, reserving them in the pool. - Rab3: involved in docking. - NSF/α-SNAP: disassemble the SNARE complex after fusion so the components can be reused. - SV2: a vesicle glycoprotein and the target of levetiracetam. - Clathrin and dynamin: mediate endocytosis and recycling.

CLINICAL CORRELATIONS: - Botulinum toxin (Clostridium botulinum) cleaves SNARE proteins (synaptobrevin, SNAP-25, syntaxin, depending on serotype). This blocks ACh release at the NMJ and causes flaccid paralysis. It is used therapeutically for dystonia, spasticity, and cosmetic indications. - Tetanus toxin (Clostridium tetani) cleaves synaptobrevin in inhibitory Renshaw interneurons after retrograde transport. This blocks GABA/glycine release and causes spastic paralysis (trismus, risus sardonicus, opisthotonos). - Lambert-Eaton myasthenic syndrome: autoantibodies against presynaptic voltage-gated Ca2+ channels reduce Ca2+-dependent vesicle release. It is associated with small cell lung cancer. Weakness improves with repeated use (facilitation), unlike myasthenia gravis, which is a postsynaptic AChR antibody disease. - Black widow spider toxin (α-latrotoxin) causes massive vesicle exocytosis and ACh release, producing muscle cramps and rigidity. - Reserpine inhibits VMAT, depleting vesicular monoamine stores. Tetrabenazine and valbenazine also inhibit VMAT2 and are used for Huntington chorea and tardive dyskinesia. - Vesamicol blocks VAChT (experimental). - Amphetamines reverse VMAT/transporter function and promote monoamine release. - Levetiracetam binds SV2A and is an antiepileptic. - Hemicholinium blocks choline uptake, which limits ACh synthesis. This is distinct from vesicle loading. - Quantal release: each vesicle releases one quantum of neurotransmitter, producing a miniature end-plate potential (MEPP) at the NMJ. The end-plate potential is the summation of many quanta.

HIGH-YIELD PEARLS: Exocytosis requires Ca2+ influx, so Mg2+ (a Ca2+ channel competitor) reduces release. This is the basis for Mg2+ treatment of preeclampsia and the risk of toxicity with loss of reflexes and respiratory depression. Vesicle membrane is retrieved by clathrin-mediated endocytosis, not simply lost to the plasma membrane.

Sources

  • First Aid for the USMLE Step 1 (Neurology/Neurophysiology and Microbiology: toxins)
  • Kandel ER et al. Principles of Neural Science
  • Costanzo Physiology
  • Pathoma (neuromuscular pathology)
  • Purves D et al. Neuroscience
  • Südhof TC. The synaptic vesicle cycle. Annu Rev Neurosci

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