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

神经元网络的正确功能依赖于神经元之间的精确连接和通信，而神经元之间的精确连接和通信是由突触介导的。因此，了解在健康和疾病中控制突触信号的分子机制是重要的。研究表明，Rab3相互作用分子(RIM)1和2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在调节突触机制的关键组件的可用性以及树突棘和神经元树枝的发育方面可能同样重要。特别是，在RIM4缺陷的小鼠中，突触缺陷似乎会导致强烈的和致残的发作性运动缺陷。在本研究中，我们希望从细胞和网络水平上进一步探讨RIM3和RIM4的功能机制，阐明目前未知的Gamma-Rims在突触传递中的分子机制。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。

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.