Neurophysiology
Synaptic Transmission
Action potential to neurotransmitter release to receptor binding — the fundamental unit of neural communication
Synapses transmit signals from one neuron to another (or to a muscle/gland) at chemical or electrical junctions. In a chemical synapse: an action potential depolarizes the presynaptic terminal, opens voltage-gated Ca²⁺ channels, triggers SNARE-mediated vesicle fusion, releases neurotransmitter into the synaptic cleft, where it diffuses ~20 nm to bind postsynaptic receptors. Ionotropic receptors (ligand-gated ion channels) produce fast EPSPs/IPSPs in milliseconds; metabotropic (GPCR) receptors produce slower G-protein–mediated effects. Major transmitters: glutamate (excitatory), GABA (inhibitory), dopamine, serotonin, norepinephrine, acetylcholine, glycine, neuropeptides. Termination via reuptake (SERT, DAT, NET), enzymatic degradation (acetylcholinesterase, MAO), or diffusion. Synaptic plasticity (LTP, LTD) underlies learning and memory.
- Cleft width~20-40 nm
- Vesicle volume~5,000 transmitter molecules per quantum
- Calcium triggerVoltage-gated Cav2.1/Cav2.2 channels
- Excitatory transmitterGlutamate (NMDA, AMPA, kainate, mGluR receptors)
- Inhibitory transmitterGABA (GABAA ionotropic, GABAB metabotropic)
- Synaptic delay~0.5 ms (Ca²⁺ entry to release)
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Why synaptic transmission matters
- Psychiatric pharmacology. SSRIs, SNRIs, antipsychotics, benzodiazepines all target synaptic transmitters and receptors.
- Neurology. Levodopa for Parkinson disease replaces dopaminergic synaptic input; anticonvulsants modulate sodium channels and GABA.
- Neuromuscular disease. Myasthenia, botulism, organophosphate poisoning all converge on the cholinergic NMJ.
- Anesthesia. General anesthetics potentiate GABAA and inhibit NMDA receptors; succinylcholine activates muscle nicotinic receptors.
- Memory and learning. LTP/LTD are cellular substrates; their dysfunction is implicated in Alzheimer disease.
- Addiction medicine. Synaptic plasticity in mesolimbic circuit explains tolerance, withdrawal, and craving.
- Toxicology. Tetanus, botulism, organophosphate, and snake toxins all target specific synaptic components.
Common misconceptions
- One neurotransmitter per neuron. Many neurons co-release multiple transmitters (glutamate + neuropeptide).
- Glutamate is a magic excitatory transmitter. Excessive glutamate causes excitotoxicity — major contributor to stroke and ALS.
- Inhibitory transmitters are always inhibitory. Early in development GABA is excitatory because of high intracellular Cl⁻.
- Reuptake inhibitors work immediately. SSRIs increase synaptic serotonin in hours but mood improvement takes weeks — downstream plasticity.
- Synapses are static structures. Synapses continuously remodel; spines appear and disappear over days.
- Chemical synapses are always faster than electrical. Chemical synapses have ~0.5 ms delay; electrical have essentially none.
Frequently asked questions
How does an action potential trigger neurotransmitter release?
Depolarization opens voltage-gated Ca²⁺ channels (P/Q and N type) in the presynaptic active zone. Local Ca²⁺ rises 10-100 µM within microdomains and binds synaptotagmin on docked vesicles. Synaptotagmin pulls vesicle and plasma membrane together, completing SNARE-mediated fusion (synaptobrevin on vesicle pairs with syntaxin and SNAP-25 on plasma membrane). Vesicles release ~5,000 transmitter molecules each. Within ~1 ms, neurotransmitter saturates postsynaptic receptors. Botulinum toxin cleaves SNAREs, blocking release; tetanus toxin similarly inhibits inhibitory synapses centrally.
What's the difference between ionotropic and metabotropic receptors?
Ionotropic receptors are ligand-gated ion channels — fast (millisecond) and synapse-localized: nicotinic ACh, AMPA/NMDA glutamate, GABAA, glycine, 5-HT3. Metabotropic receptors are GPCRs that activate G-protein cascades — slower (100 ms-seconds) and modulatory: muscarinic ACh, mGluR, GABAB, dopamine D1-D5, most serotonin, adrenergic. Metabotropic effects can persist long after transmitter clears, modulating excitability and gene expression.
How is neurotransmission terminated?
Mechanisms vary. Reuptake by transporters: SERT (serotonin), DAT (dopamine), NET (norepinephrine), GAT (GABA), EAAT (glutamate). Enzymatic degradation: acetylcholinesterase hydrolyzes ACh in cleft (myasthenia gravis treated with pyridostigmine inhibitor); monoamine oxidase and COMT degrade catecholamines and serotonin intracellularly. Diffusion away from cleft. Drugs targeting these: SSRIs block SERT; cocaine blocks DAT; MAO inhibitors block degradation; organophosphates inhibit acetylcholinesterase causing cholinergic crisis.
What is long-term potentiation?
LTP is the persistent strengthening of synaptic transmission after repeated activation — a cellular substrate of learning. In hippocampal CA1: high-frequency stimulation depolarizes the postsynaptic neuron sufficiently to expel Mg²⁺ block from NMDA receptors, allowing Ca²⁺ entry. Ca²⁺ activates CaMKII which phosphorylates and inserts more AMPA receptors. Late-phase LTP requires gene transcription and new protein synthesis. LTD (long-term depression) weakens synapses through opposing mechanisms; balance shapes memory.
How do drugs of abuse hijack synapses?
Most drugs of abuse increase dopamine in the nucleus accumbens. Cocaine and amphetamines block DAT (and amphetamines reverse it, dumping dopamine). Opioids inhibit GABA interneurons via mu receptors, disinhibiting VTA dopamine neurons. Nicotine activates nicotinic receptors on dopamine neurons. Alcohol potentiates GABAA and inhibits NMDA. Repeated activation drives plasticity in mesolimbic circuit, producing tolerance, sensitization, and craving. Addiction reflects long-term synaptic changes.
What is the neuromuscular junction?
Specialized cholinergic synapse where motor neurons control skeletal muscle. Action potential at terminal releases acetylcholine; ACh binds nicotinic receptors on motor end plate; depolarization triggers muscle action potential and contraction. Acetylcholinesterase rapidly clears ACh. Diseases: myasthenia gravis (autoantibodies against ACh receptor — fatigable weakness, treated with pyridostigmine and immunosuppression); Lambert-Eaton (antibodies against presynaptic Cav2.1 channels, often paraneoplastic from small cell lung cancer); botulism (toxin blocks ACh release).
Why are some synapses electrical?
Electrical synapses use gap junctions (connexin hexamers) to allow direct cytoplasmic and ionic continuity between cells. Bidirectional, rapid (<0.1 ms), no synaptic delay. Used where speed and synchrony matter: cardiac myocytes, smooth muscle, retinal cells, certain hippocampal interneurons coordinating gamma oscillations. Faster but lack the modulation, gain, and plasticity of chemical synapses. Most CNS synapses are chemical.