When an action potential reaches the end of an axon, it does not jump to the next neuron — axons and dendrites are not in physical contact. There is a gap, the synaptic cleft, about 20 nanometres wide. Otto Loewi dreamed the experiment that proved how signals cross: in 1921 on isolated frog hearts, he showed the vagus nerve slowed the heart by releasing a chemical substance (his Vagusstoff, later identified as acetylcholine) — Nobel 1936, shared with Henry Dale. Synaptic transmission — chemical conversion of an electrical signal across the gap — is the fundamental signaling event of the nervous system, repeated on the order of a quadrillion times per second in a human brain.
At the presynaptic terminal the action potential opens voltage-gated calcium channels; calcium triggers synaptic vesicles containing neurotransmitter molecules to fuse with the membrane and dump their contents into the synaptic cleft. The molecules diffuse across in microseconds and bind receptors on the postsynaptic membrane. Ionotropic receptors are themselves ion channels (fast, direct). Metabotropic receptors couple to G-proteins and run intracellular cascades (slower, modulatory). Excitatory synapses depolarize the postsynaptic cell; inhibitory synapses hyperpolarize it. Glutamate dominates excitation in the mammalian brain; GABA dominates inhibition. Modulatory neurotransmitters — dopamine, serotonin, norepinephrine, acetylcholine — act mostly metabotropically over slower timescales. Released neurotransmitter is cleared by reuptake (transporters pumping it back — what SSRIs like fluoxetine block for serotonin), enzymatic degradation (acetylcholinesterase, blocked by sarin), or diffusion. Synaptic strength is not fixed: it can be increased (long-term potentiation) or decreased (long-term depression) on timescales from seconds to lifetimes — the synaptic plasticity that underwrites learning and memory. Most psychiatric drugs act at synapses: antidepressants on serotonin/norepinephrine reuptake; antipsychotics on dopamine receptors; benzodiazepines on GABA; opioids on opioid receptors; stimulants on dopamine/norepinephrine. The psychopharmacological revolution of the 1950s–60s — chlorpromazine, lithium, imipramine, benzodiazepines — was synaptic chemistry's clinical working-out.
Optogenetic and chemogenetic tools let researchers manipulate specific synapse types in behaving animals — a methodological capability that has transformed circuit-level neuroscience since ~2010. Connectomics — the cataloguing of synapses — is now advanced enough in flies and small mouse regions to enable circuit-level computational modeling. More than 20% of all drugs in clinical use act at synaptic targets, and the next generation of psychiatric medication (psychedelics — psilocybin, MDMA, ketamine) is essentially a re-exploration of synaptic chemistry from a different angle. Brain-computer interfaces will eventually need to read and write at the synaptic level to be truly bidirectional.