Timing of neurotransmission at fast synapses in the mammalian brain

UNDERSTANDING the factors controlling synaptic delays has broad implications. On a systems level, the speed of synaptic transmission limits the communication rate between neurons and strongly influences local circuit dynamics1,2. On a molecular level, the delay from presynaptic calcium entry to postsynaptic responses constrains the molecular mechanism of vesicle fusion3. Previously it has not been possible to elucidate the determinants of synaptic delays in the mammalian central nervous system, where presynaptic terminals are small and difficult to study. We have developed a new approach to study timing at rat cerebellar synapses: we used optical techniques to measure voltage and calcium current simultaneously from presynaptic boutons while monitoring postsynaptic currents electrically4–6. Here we report that the classic view that vesicle release is driven by calcium entry during action-potential repolarization7 holds for these synapses at room temperature, but not at physiological temperatures, where postsynaptic responses commence just 150 μs after the start of the presynaptic action potential. This brisk communication is a consequence of rapid calcium-channel kinetics, which allow significant calcium entry during the upstroke of the presynaptic action potential, and extremely fast calcium-driven vesicle fusion, which lags behind calcium influx by 60 μs.