Synaptic Transmission

Synaptic transmission is the physiological process by which a neuron communicates across a specialized junction (synapse) with a target neuron, muscle fiber, or gland cell. Named by Sir Charles Sherrington in 1897 (from the Greek synapsis, "conjunction"), synapses across the metazoan nervous system fall into two structurally and biophysically distinct classes.

1. Electrical Synapses: Direct, bidirectional low-resistance cytoplasmic bridges formed by gap junction channels (connexin-36 hemichannels in vertebrates; innexins in invertebrates) across a narrow ~3.5 nm intercellular gap. Electrical synapses transmit ionic current instantaneously (synaptic delay <0.05 ms) to synchronize interneuron oscillations, cardiac pacemaking, and escape reflexes.
2. Chemical Synapses: Unidirectional junctions across a 20–30 nm synaptic cleft (in the central nervous system) where a presynaptic action potential opens voltage-gated calcium channels (Ca_V2.1 [P/Q-type] and Ca_V2.2 [N-type]), triggering sub-millisecond SNARE- and synaptotagmin-1-mediated exocytosis of neurotransmitter-filled synaptic vesicles. Released neurotransmitter molecules diffuse across the cleft in <50 μs to bind ionotropic or metabotropic receptors anchored within the postsynaptic density (PSD), converting the chemical signal back into an excitatory or inhibitory electrical potential (EPSP or IPSP) with a characteristic synaptic delay of 0.3–1.5 ms.

Elucidated by James Rothman, Randy Schekman, and Thomas Südhof (2013 Nobel Prize in Physiology or Medicine), fast Ca²⁺-evoked synaptic vesicle exocytosis is driven by the neuronal SNARE complex and its regulatory clamps:

1. The Four-Helix SNARE Bundle and Zero-Layer Ionic Tetrad

At the core of the membrane fusion engine is an exceptionally stable four-helix parallel coiled-coil bundle assembled from three SNARE proteins:

• Synaptobrevin-2 (VAMP2): A single-pass vesicular membrane protein (R-SNARE) that contributes one α-helix containing a conserved central arginine (R) residue at the hydrophilic "zero layer."
• Syntaxin-1A/1B: A plasma membrane protein (Qa-SNARE) that contributes one α-helix containing a central glutamine (Q) residue. In isolation, syntaxin-1 adopts a closed, autoinhibited conformation bound by Munc18-1 (STXBP1); active-zone Munc13-1 (UNC13A) catalyzes the opening of syntaxin-1 so the SNARE complex can nucleate.
• SNAP-25: A palmitoylated peripheral plasma membrane protein (Qbc-SNARE) that contributes two α-helices, each supplying a central glutamine (Q) residue (3Q : 1R ionic zero layer buried inside 15 hydrophobic leucine-zipper layers).

Zippering of the four helices from their N-termini toward their C-terminal transmembrane anchors releases ~35–65 k_BT of free energy, pulling the negatively charged vesicular and plasma membranes within <1 nm to overcome the hydration repulsion barrier and open a fusion pore.

2. Synaptotagmin-1 and the Fourth-Power Calcium Cooperativity of Release

As demonstrated by Bernard Katz and Ricardo Miledi (and quantified by Erwin Neher and Bert Sakmann), neurotransmitter release rate scales with the fourth to fifth power of local intracellular calcium concentration (Release Rate ∝ [Ca²⁺]_i⁴). This steep cooperativity is mediated by Synaptotagmin-1 (SYT1) (or Synaptotagmin-2 at ultra-fast auditory calyx of Held and neuromuscular synapses), a vesicular transmembrane protein bearing two cytoplasmic C2 domains (C2A and C2B) that coordinate a total of five Ca²⁺ ions via acidic aspartate loops. Prior to action-potential arrival, the C2B domain of Synaptotagmin-1 and the accessory protein Complexin-1 clamp the partially zippered trans-SNARE complex in a metastable primed state; upon Ca²⁺ binding, the C2A/C2B loops insert into PIP₂-rich active-zone patches, releasing the clamp and triggering synchronous exocytosis in <100–200 μs.

Once released into the synaptic cleft, a neurotransmitter acts on two superfamilies of postsynaptic receptors—fast ionotropic (ligand-gated ion channels) and slower, modulatory metabotropic (G-protein-coupled receptors, GPCRs)—before being cleared within milliseconds by Na⁺/Cl⁻-coupled plasma membrane transporters (EAAT1–5 for glutamate; GAT1–3 for GABA; DAT, NET, SERT for monoamines) or enzymatic hydrolysis:

Whether a postsynaptic conductance change is excitatory or inhibitory depends specifically on the relationship between the channel's reversal potential (E_rev) and the postsynaptic action-potential threshold (V_thresh ≈ −50 to −55 mV):

• Excitatory Postsynaptic Potentials (EPSPs): Opening of AMPA or NMDA glutamate receptors (E_rev ≈ 0 mV) drives inward Na⁺ (and Ca²⁺) current that depolarizes the dendrite toward V_thresh. Individual cortical unitary EPSPs are small (0.2–2.0 mV), requiring spatial summation (simultaneous inputs across multiple dendritic spines) and temporal summation (high-frequency inputs arriving within the membrane time constant τ_m = R_mC_m ≈ 10–30 ms) to trigger an action potential at the axon initial segment (AIS).
• Hyperpolarizing and Shunting Inhibitory Postsynaptic Potentials (IPSPs): In mature neurons—where the K⁺–Cl⁻ cotransporter KCC2 (SLC12A5) extrudes Cl⁻ to maintain a low intracellular [Cl⁻]_i (~4–6 mM)—the chloride Nernst equilibrium potential E_Cl is −70 to −75 mV (below V_thresh). Opening of GABA_A or Glycine receptors therefore hyperpolarizes the neuron or clamps its membrane potential near −70 mV while dropping membrane input resistance R_m (shunting inhibition: by Ohm's law, ΔV = I_EPSP · R_m, so opening somatic GABA_A conductances short-circuits incoming dendritic excitatory currents before they can reach the axon initial segment). *(Note: In immature fetal/neonatal neurons, high expression of the Na⁺–K⁺–2Cl⁻ importer NKCC1 and low KCC2 keep [Cl⁻]_i high (~25 mM, E_Cl ≈ −40 mV), making neonatal GABAergic transmission transiently depolarizing until the postnatal NKCC1-to-KCC2 developmental switch).*

• Südhof, T. C. (2013). Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron, 80(3), 675–690. Google Scholar
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