When a typical glutamate-containing neurone fires, an action potential is propagated down the branching axon through more than a thousand varicosities. At each of these release sites the probability that a synaptic vesicle will be exocytosed into the synaptic cleft is individually controlled by means of presynaptic receptors: autoreceptors responding by positive or negative feedback to previously released transmitter, or heteroreceptors under the influence of other neurotransmitters or modulators. The simplest system in which to investigate presynaptic modulation is the isolated nerve terminal or synaptosome; studies with this preparation have revealed a complex interplay of signal-transduction pathways.