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

RIM4 依赖性突触病导致新型发作性共济失调：分子机制和改变的电路功能

• 批准号: 318583703
• 负责人: Professor Dr. Dirk Dietrich
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318583703?language=en
• 关键词: RIM4; dependent; synaptopathy; causing; novel

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.

神经元网络的正确功能依赖于神经元之间的精确连接和交流，而突触是神经元之间准确连接和交流的中介。因此，了解在健康和疾病中控制突触信号的分子机制是很重要的。Rab3相互作用分子（RIM） 1和2已被证明对正常突触功能至关重要。我们的初步数据表明，RIM蛋白家族的短变体RIM4和RIM3可能在调节突触机制关键成分的可用性以及树突棘和神经元树突的发育方面同样重要。特别是，在RIM4缺陷小鼠中，突触缺陷似乎会导致强烈的、致残的偶发性运动缺陷。在本课题中，我们希望在细胞和网络水平上进一步探索RIM3和RIM4的功能机制，并阐明gamma-RIMs在突触传递中的作用目前尚不清楚的分子机制。这些实验的结果将为突触传递和神经元网络功能的动态调节的一般机制以及突触特性对正常运动控制的重要性提供新的见解。