synaptic cleft

**Structure:** The synaptic cleft separates the presynaptic axon terminal from the postsynaptic membrane (dendrite, soma, or muscle fiber). It is about 20–40 nm wide at central synapses and wider (~50–100 nm) at the neuromuscular junction (NMJ). It is filled with extracellular matrix, including proteoglycans and adhesion proteins (neurexin–neuroligin, cadherins). The NMJ cleft also contains a basal lamina rich in acetylcholinesterase (AChE).

**Sequence of chemical transmission:** 1. An action potential depolarizes the presynaptic terminal. 2. Voltage-gated Ca²⁺ channels open and Ca²⁺ enters. 3. Ca²⁺ triggers SNARE-mediated vesicle fusion (synaptobrevin/VAMP, syntaxin, SNAP-25; synaptotagmin is the Ca²⁺ sensor), and neurotransmitter is released by exocytosis into the cleft. 4. Neurotransmitter diffuses across the cleft and binds postsynaptic ionotropic (ligand-gated ion channel) or metabotropic (GPCR) receptors, producing an EPSP or IPSP. 5. The signal is terminated.

**Termination of signaling in the cleft:** - **Enzymatic degradation:** AChE breaks down ACh into acetate and choline, and choline is taken back up by the presynaptic terminal. COMT and MAO degrade catecholamines. - **Reuptake:** Presynaptic transporters (NET, DAT, SERT, and others) remove transmitter from the cleft. Astrocytes take up glutamate (EAAT) and GABA. - **Diffusion** away from the cleft.

**Clinical and pharmacologic correlations (high-yield):** - **Botulinum toxin** cleaves SNARE proteins, blocking ACh release and causing flaccid paralysis. - **Tetanus toxin** cleaves SNARE proteins in inhibitory Renshaw interneurons (blocking GABA/glycine release), causing spastic paralysis. - **Acetylcholinesterase inhibitors** (neostigmine, pyridostigmine, physostigmine, edrophonium) increase ACh in the cleft. They are used for myasthenia gravis, reversal of nondepolarizing neuromuscular blockade, and Alzheimer disease (donepezil). Organophosphates cause irreversible AChE inhibition, leading to cholinergic toxicity (DUMBBELSS). The antidotes are atropine and pralidoxime. - **Myasthenia gravis:** Autoantibodies against postsynaptic nicotinic ACh receptors cause fatigable weakness. Associations are thymoma and thymic hyperplasia. - **Lambert-Eaton syndrome:** Antibodies against presynaptic voltage-gated Ca²⁺ channels reduce ACh release. It is associated with small cell lung cancer, and strength improves with repeated use. - **Reuptake inhibitors** raise cleft neurotransmitter levels: SSRIs, SNRIs, TCAs, cocaine (blocks DAT, NET, SERT), and amphetamines (promote release and reverse transporters). - **MAO inhibitors** increase presynaptic stores of monoamines. - **Electrical synapses** (gap junctions, connexons) have no true synaptic cleft (~3.5 nm gap), allow bidirectional rapid transmission, and are found in cardiac and smooth muscle.

**Other points for boards:** Chemical synapses are unidirectional, with a synaptic delay (~0.5 ms) because of the Ca²⁺-dependent release and diffusion steps. Cleft width and transmitter clearance determine how fast and how long the postsynaptic response lasts.