RIM4 dependent synaptopathy causing a novel form of episodic ataxia: molecular mechanisms and altered circuit function

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The correct function of neuronal networks relies on the precise connectivity and communication between neurons, which is mediated by synapses. Therefore, it is important to understand the molecular mechanisms that control synaptic signaling in health and disease. Rab3 interacting molecules (RIM) 1 and 2 have been shown to be crucial for normal synaptic function. Our preliminary data indicates that the short variants of the RIM protein family, RIM4 and RIM3, may be equally important in regulating the availability of key components of the synaptic machinery as well as in the development of dendritic spines and of neuronal arborization. In particular, in RIM4 deficient mice the synaptic deficit seems to cause a strong and disabling episodic motor deficit. In this proposal we want to further explore the mechanism of RIM3 and RIM4 function on the cellular and network level and elucidate the currently unknown molecular mechanism of gamma-RIMs action in synaptic transmission. The results of these experiments should provide novel insights both into the general mechanisms underlying the dynamic regulation of synaptic transmission and neuronal network function as well as into the importance of synaptic properties for normal motor control.