How Ephexin Signaling Promotes Neuronal Stability

目的：一些神经系统疾病的原因和进展受到控制神经功能稳定性的因素的影响。 然而，支配神经兴奋和抑制的机制却知之甚少。 许多研究表明，稳态信号机制参与神经功能的调节，特别是通过调节突触连接的强度。 本项目旨在阐明突触稳态信号传导的机制。 背景/原理：我们发表了一项研究，证明了Ephexin信号系统在突触稳态中的作用。 Ephexin是Rho型鸟嘌呤交换因子（GEF）。 果蝇Ephexin是突触前所需的突触稳态和定位在附近的其他组件的神经末梢。 在Ephexin GEF功能的下游，Rho型GTP酶对于执行稳态补偿是重要的，特别是Cdc 42。 在Ephexin的上游，果蝇Eph受体（Eph）结合Ephexin，并且Eph突变体具有受损的突触稳态。 该信号系统的组件显示出彼此之间以及与CaV2.1钙通道突变体之间的强烈遗传相互作用。 我们推测，这突触前信号系统耦合稳态逆行信号在突触质膜的调制突触前CaV2.1功能和神经递质释放。 R 00阶段设计：在其他系统中已知的调节钙通道功能和Eph/Ephexin/GTP信号传导的候选分子将被测试在突触稳态中的作用。 在体内平衡中发挥作用的分子将被置于我们的突触前信号系统的背景下。 这项工作将利用三年R 00阶段的方法组合：突触功能的电生理学分析，遗传突变分析，靶分子的药理学抑制，基因表达和蛋白质定位分析，转基因拯救，遗传上位性和途径分析。 受训人员：我实验室新招募的成员将接受本项目各方面的培训。 在三年的时间里，这可能包括一名技术人员，两名研究生和一名博士后研究员。

OBJECTIVE: The causes and progression of several neurological diseases are influenced by factors that control the stability of neural function. Yet the mechanisms that dictate neural excitation and inhibition are poorly understood. Many studies indicate that homeostatic signaling mechanisms participate in the regulation of neural function, in particular by modulating the strength of synaptic connections. This project aims to clarify the mechanisms of synaptic homeostatic signaling. BACKGROUND/RATIONALE: We published a study demonstrating a role in synaptic homeostasis for an Ephexin signaling system. Ephexin is a Rho-type guanine exchange factor (GEF). Drosophila Ephexin is required presynaptically for synaptic homestasis and localizes in proximity of other components of the nerve terminal. Downstream of Ephexin GEF function, Rho-type GTPases are important for executing homeostatic compensation, in particular Cdc42. Upstream of Ephexin, the Drosophila Eph receptor (Eph) binds Ephexin and Eph mutants have impaired synaptic homeostasis. Components of this signaling system show strong genetic interactions with each other and with CaV2.1 calcium channel mutants. We postulate that this presynaptic signaling system couples homeostatic retrograde signaling at the synaptic plasma membrane to the modulation of presynaptic CaV2.1 function and neurotransmitter release. R00 PHASE DESIGN: Candidate molecules already known in other systems to regulate calcium channel function and Eph/Ephexin/GTP signaling will be tested for roles in synaptic homeostasis. Molecules that do show a role in homeostasis will be placed into the context of our presynaptic signaling system. This work will utilize a combination of approaches for the three-year R00 phase: electrophysiological analysis of synaptic function, genetic mutant analyses, pharmacological inhibition of target molecules, analyses of gene expression and protein localization, transgenic rescue, and genetic epistasis and pathway analyses. TRAINEES: New recruited members of my laboratory will be trained in all aspects of this project. Over the course of three years, this may include a technician, two graduate students, and a postdoctoral fellow.