NF186 in GABAergic domain specific synaptic targeting

描述（由申请人提供）：gaba能抑制在神经网络特性的许多方面发挥重要作用，从神经元兴奋性到同步性。不同类别的gaba能突触被分离到亚细胞区域（即树突、体、轴突初始段- ais），从而不同地调节主神经元的输入、整合和输出。gaba能突触的亚细胞靶向机制仍然很大程度上未知。我们实验室最近的工作已经证明了L1家族免疫球蛋白细胞粘附分子（IgCAM）， neurofascin186 （NF186）及其潜在的基于锚定的膜骨架在靶向gaba能突触到小脑浦肯野神经元AIS中的重要作用。本研究假设NF186的亚细胞定位和信号传导是gaba能神经支配主要神经元（如新皮层锥体神经元）的躯体/AIS的一般机制。我们将通过研究NF186在gaba能突触靶向过程中的空间和时间表达，并通过遗传、生化和成像方法的结合来操纵NF186的分布和功能，来验证这一假设。

DESCRIPTION (provided by applicant): GABAergic inhibition plays important roles in many aspects of neural network properties ranging from neuronal excitability to synchrony. Distinct classes of GABAergic synapses are segregated into subcellular domains (i.e. dendrite, soma, axon initial segment-AIS), thereby differentially regulating the input, integration and output of principal neurons. The mechanisms underlying the subcellular targeting of GABAergic synapses remain largely unknown. Recent work in our laboratory has demonstrated an essential role for an L1 family immunoglobulin cell adhesion molecule (IgCAM), neurofascin186 (NF186) and its underlying ankyrinG-based membrane skeleton in the targeting of GABAergic synapses to AIS of Purkinje neurons in cerebellum. Here we hypothesize that the subcellular localization and signaling of NF186 is a general mechanism which directs GABAergic innervation to soma/AIS of principal neurons, such as pyramidal neurons in neocortex. We will test this hypothesis by examining the spatial and temporal expression of NF186 during GABAergic synapse targeting, and by manipulating the distribution and function of NF186 through a combination of genetic, biochemical and imaging approaches.