The sequence of events that underlie quantal transmission at central glutamatergic synapses

Key Points There has been remarkable recent progress in our understanding of the sequence of steps that mediate chemical transmission at mammalian central glutamatergic synapses. This work provides insight into how neurotransmitter is released and how the quantal response is generated. Work on large central synapses has made it possible to voltage-clamp the presynaptic terminal, to control the Ca 2+ concentration and to monitor release. This work confirms earlier studies in the squid giant axon showing that the current through voltage-dependent Ca 2+ channels that triggers release occurs on the falling phase of the action potential. The Ca 2+ that triggers release occurs in a microdomain near the Ca 2+ channels. This Ca 2+ elevation is sensed by the molecule synaptotagmin 1. It appears that the synaptic vesicle membrane is already partially fused with the plasma membrane and awaits the activation of synaptotagmin. When this occurs, a fusion pore opens. Whether this pore is like a protein channel or is lipid-lined remains to be resolved. The size of the fusion pore can vary and this determines the rate at which the neurotransmitter diffuses into the synaptic cleft. Modulation of fusion pore size is likely to be important for regulation. The resulting activation of AMPA channels in the postsynaptic membrane depends on the channel's properties and much has been learnt about this through structural, molecular and electrophysiological experiments. Glutamate can cause either activation or inactivation of AMPA channels. To be effectively activated, the glutamate concentration in the synaptic cleft must be high, a condition that only holds near the site of vesicle release. Each vesicle that is released generates a quantal response in the postsynaptic cell. Many of the factors that shape the quantal response and make it reproducible are now understood. At some synapses multiple vesicles are released, allowing fluctuations in transmission efficacy. Synaptic transmission is temporally and spatially tightly regulated to serve the needs of fast information flow in the nervous system. Lisman and colleagues bridge the synaptic cleft and review the sequence of pre- and postsynaptic events of quantal release. The properties of synaptic transmission were first elucidated at the neuromuscular junction. More recent work has examined transmission at synapses within the brain. Here we review the remarkable progress in understanding the biophysical and molecular basis of the seq