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起着重要作用，从神经元的兴奋性到同步性。不同类型的GABA能突触被分成亚细胞域(即树突、胞体、轴突初始段-AIS)，从而对主神经元的输入、整合和输出进行不同的调节。GABA能突触亚细胞靶向的机制在很大程度上仍不清楚。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黏附分子(IgCAM)，Neuroseon186(NF186)及其基于G的膜骨架在将GABA能突触靶向小脑浦肯野神经元AIS的过程中发挥了重要作用。我们推测，NF186的亚细胞定位和信号传递是将GABA能神经支配到主神经元(如大脑皮层锥体神经元)的一般机制。我们将通过检测在GABA能突触靶向过程中NF186的空间和时间表达，以及通过结合遗传、生化和成像方法来操纵NF186的分布和功能来检验这一假说。

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.