Synaptotagmin IV (Syt IV) is an activity-inducible, secretory vesicle protein that is thought to function as an inhibitor of neurotransmitter release (Littleton et al. Nature 400:757-760, 1999). To test this hypothesis in neurons of the mammalian CNS, we measured field excitatory postsynaptic potentials (fEPSPs) in hippocampal slice preparations from Syt IV (-/-) mice. At Schaffer collateral synapses, the basal properties of neurotransmission are largely normal. However, two forms of short-term plasticity, paired-pulse facilitation (PPF) and post-tetanic potentiation (PTP), are significantly enhanced in area CA1 of Syt IV (-/-) slices. Similarly, the early stages of long-term potentiation (LTP) are also enhanced at these synapses. Consistent with the low levels of Syt IV observed in dentate granule cells, the mossy fiber synapses in Syt IV (-/-) slices display largely normal PPF and LTP. In addition, we find that Syt IV (-/-) mice have deficits in the associative passive avoidance memory paradigm, but are normal in the novel object recognition paradigm. The synaptic architecture and connectivity of Syt IV (-/-) brains is indistinguishable from wild-type mice as indicated by immunohistochemical analysis. These results suggest Syt IV is a presynaptic negative regulator of short-term plasticity in area CA1 of the hippocampus and is required for some, but not all, forms of hippocampus-dependent memory.
2004 Wiley-Liss, Inc.