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能突触被分成亚细胞结构域（即树突、索马、轴突起始段-AIS），从而差异地调节主要神经元的输入、整合和输出。GABA能突触的亚细胞靶向机制仍不清楚。我们实验室最近的工作表明，L1家族免疫球蛋白细胞粘附分子（IgCAM），神经纤维素186（NF 186）和其潜在的基于ankrexG的膜骨架在靶向小脑浦肯野神经元AIS的GABA能突触中起着重要作用。在此我们假设NF 186的亚细胞定位和信号传导是将GABA能神经支配引导至主要神经元（如新皮质中的锥体神经元）的索马/AIS的一般机制。我们将通过检查NF 186在GABA能突触靶向过程中的空间和时间表达，以及通过遗传、生物化学和成像方法的组合操纵NF 186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.