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，而神经元之间的连接和通信是由突触介导的。因此，了解控制健康和疾病中突触信号传导的分子机制非常重要。Rab 3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，RIM 4和RIM 3，在调节突触机制的关键成分的可用性以及树突棘和神经元分支的发育中可能同样重要。特别是，在RIM 4缺陷小鼠中，突触缺陷似乎会导致强烈的和致残的偶发性运动缺陷。在这个提议中，我们希望进一步探索RIM 3和RIM 4在细胞和网络水平上的功能机制，并阐明目前未知的γ-RIMs在突触传递中作用的分子机制。这些实验的结果应该提供新的见解，无论是到一般的机制，突触传递和神经网络功能的动态调节，以及到正常的电机控制的重要性突触属性。

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.