Project Summary The ultimate goal of this grant is to determine how synapses and circuits function in vivo to control behaviors. One major focus is to clarify the mechanisms of short-term plasticity, and to understand the functional and behavioral role of short term plasticity at different synapses. Although synaptic plasticity plays a crucial role throughout the brain, and dysfunction has been implicated in numerous neurological disorders, the many interacting forms of plasticity remain poorly understood. We will focus on the hypothesis that specialized calcium sensors respond to presynaptic calcium signals to enhance neurotransmitter release. Our findings suggest that facilitation and posttetanic potentiation (PTP) use 2 different types of calcium sensors to enhance transmission on different time scales. Facilitation is a form of synaptic enhancement that lasts for hundreds of milliseconds. We have found that facilitation is mediated by synaptotagmin 7 (syt7), which is a calcium- sensitive isoform with slow kinetics. In preliminary studies we find that in syt7 knockout mice, facilitation is eliminated even though the initial probability of release and presynaptic calcium signals are unaltered. Viral expression of syt7 restores facilitation in syt7 knockout animals. These studies indicate that we have identified the long sought after calcium sensor for facilitation. Future studies will clarify the role of syt7 in facilitation in contributing to different behaviors. PTP is a form of synaptic enhancement lasting for tens of seconds following a period of high-frequency firing of presynaptic neurons. We have recently shown that PKCβ is a calcium sensor for PTP at the calyx of Held. We will continue to clarify the mechanism of PTP and ultimately plan to use molecular genetics to selectively eliminate PTP from specific synapses to determine the role of PTP in different behaviors. A second major focus is to clarify cerebellar circuitry and understand how different circuit elements contribute to cerebellar function, which regulates motor learning, sensorimotor integration and social behaviors. We have recently shown that all Purkinje cells (PCs) have collaterals that target many types of cells within the cerebellar cortex, even in adults. This indicates it is necessary to consider feedback from the output of PCs to the cerebellar cortex. We will determine if PCPC synapses promote synchronous activity also test the hypothesis that synaptically-connected PCs converge onto the same DCN neuron and regulate its firing. These studies will extend our understanding of cerebellar processing and will provide important insights into neurological disorders that arise from cerebellar dysfunction. We will also determine how specific regions of the cerebellar cortex regulate specific behaviors.