Long-lasting neural circuit modifications are thought to underlie all forms of adaptive and pathological experience-dependent plasticity. Thus there has been great interest in elucidating the mechanisms and functions of various forms of synaptic plasticity. While historically NMDA receptor-dependent long-term potentiation (LTP) has been the prototypic and most extensively studied form of long-lasting synaptic plasticity, it is clear that several key circuits in the mammalian brain express an NMDA receptor-independent form of LTP that is triggered by increases in cAMP and mediated by a long-lasting enhancement of neurotransmitter release. The central goal of this program project is to elucidate the molecular mechanisms and functions of this presynaptic form of LTP. This will be accomplished by analyzing the functional properties of the presynaptic active zone protein RIM to both presynaptic forms of plasticity as well as its contribution to learning and memory in the cerebellum. We have assembled four projects to accomplish these goals. In project #1, we propose a biochemical and genetic analysis of RIM to elucidate the contributions that individual RIM isoforms and domains make to RIM function. In project #2, we will utilize electrophysiological approaches to assess the physiological functions of RIM isoforms and discrete RIM domains to different forms of presynaptic plasticity. In project #3, we propose a set of cellular and dynamic imaging studies to examine how RIM proteins regulate the dynamics of key active zone proteins in response to synaptic activity. Finally, in project #4, we proposed to integrate these RIM structure function studies to assess the role that presynaptic forms of plasticity contribute to VOR plasticity in the mouse cerebellum. These studies will advance our understanding of not only how RIM proteins regulate neurotransmitter release, but also how presynaptic forms of long-lasting plasticity contribute to both neural circuit behavior and experience dependent plasticity.
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