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

• Applicants: Professor Dr. Dirk Dietrich; Professorin Dr. Susanne Schoch McGovern
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318583703

This research project aims to elucidate the function of the less studied RIM family member, RIM4, which we have shown to play a critical role in Purkinje cells (PCs) of the cerebellum. Initial findings showed that RIM4 knockout (KO) mice exhibit severe motor impairments, which are not observed in other RIM isoform KOs, suggesting a unique function for RIM4. Detailed analyses revealed no significant presynaptic alterations upon RIM4 deletion, but rather suggested a somatodendritic role in PCs. RIM4 KO in PCs resulted in underdeveloped dendrites, altered intrinsic excitability, and reduced tonic firing frequency, leading to reduced inhibitory tone in deep cerebellar nucleus neurons and spontaneous motor episodes. This phenotype closely resembles paroxysmal non-kinesigenic dyskinesia (PNKD) in human patients and the phenotype of mice expressing mutant PNKD protein, which we now report binds more strongly to RIM4. Based on these observations, we hypothesize that mutant PNKD sequesters RIM4, mimicking RIM4 deficiency and leading to similar motor dysfunction. The project will address several aims: identifying RIM4 sequences critical for PC function and normal motor behavior, defining its subcellular localization, analyzing RIM4-dependent signaling changes via a multi- and trans-omics approach, and examining the time course of alterations of RIM4 deficiency. In addition, a novel pathophysiological mechanism of PNKD involving the induction of RIM4 deficiency and gene therapy approaches for PNKD will be tested.

• DFG Programme: Research Grants