Control of inhibitory synaptic transmission by the splicing regulator Rbfox1

 描述(由申请人提供)：RNA结合蛋白(RBPs)的转录后调控是许多对正常神经元功能至关重要的过程的基础。大脑丰富的RBP RBFOX1调节失调与严重的神经系统疾病有关，如癫痫和自闭症谱系障碍。虽然RBFOX1对突触功能的调节被认为与这些疾病有关，但了解RNA水平的变化如何影响神经生理的努力仍处于起步阶段，RBFOX1调节的机制尚不清楚。为了理解复杂的神经系统疾病的长期目标，需要在细胞和分子水平上仔细研究RBFOX1对突触功能的调节。我们已经确定了一个RBFOX1靶点Vamp1，它可能参与抑制性突触传递。我们假设RBFOX1通过以细胞类型特异性的方式在转录后水平调控Vamp1来控制神经元的兴奋性。我们将结合电生理学 和小鼠神经元中的生化方法：1)确定Vamp1在RBFOX1基因敲除中的功能；2)确定RBFOX1调节Vamp1转录水平的机制。这些研究将提供对RBFOX1功能和细胞类型特异性的机械性见解 转录后调控，为了解严重神经系统疾病的分子基础奠定基础。

 DESCRIPTION (provided by applicant): Post-transcriptional regulation by RNA-binding proteins (RBPs) underlies many processes critical for proper neuronal function. Dysregulation of the brain-enriched RBP Rbfox1 has been linked to serious neurological diseases such as epilepsy and autism spectrum disorders. While Rbfox1 regulation of synaptic function is thought to contribute to these diseases, efforts to understand how RNA-level changes affect neuronal physiology remain in their infancy, and the mechanism of Rbfox1 regulation is not yet well understood. The long-term goal of understanding complex neurological diseases will require careful investigation of Rbfox1 regulation of synaptic function at the cellular and molecular level We have identified an Rbfox1 target, Vamp1, which may be involved in inhibitory synaptic transmission. We hypothesize that Rbfox1 controls neuronal excitability by regulating Vamp1 at the post-transcriptional level in a cell-type specific manner. We will combine electrophysiological and biochemical approaches in mouse neurons to 1) Determine the function of Vamp1 in the Rbfox1 knockout and 2) Define the mechanism by which Rbfox1 regulates Vamp1 transcript levels. These studies will provide mechanistic insight into Rbfox1 function and cell- type specific post-transcriptional regulation and lay the foundation for understanding the molecular basis of serious neurological diseases.