Repetitive activation of excitatory synapses in the central nervous system results in a long-lasting increase in synaptic transmission called long-term potentiation (LTP). It is generally believed that this synaptic plasticity may underlie certain forms of learning and memory. LTP at most synapses involves the activation of the NMDA (N-methyl-D-aspartate) subtype of glutamate receptor, but LTP at hippocampal mossy fibre synapses is independent of NMDA receptors and has a component that is induced and expressed presynaptically. It appears to be triggered by a rise in presynaptic Ca2+ (refs 2, 3), and requires the activation of protein kinase A, which leads to an increased release of glutamate. A great deal is known about the biochemical steps involved in the vesicular release of transmitter, but none of these steps has been directly implicated in long-term synaptic plasticity. Here we show that, although a variety of short-term plasticities are normal, LTP at mossy fibre synapses is abolished in mice lacking the synaptic vesicle protein Rab3A.
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