Astrocytes and inhibitory synaptogenesis

描述（由申请人提供）：我打算研究星形胶质细胞调节发育中中枢神经系统抑制性突触发生的机制。先前的工作和体外海马神经元的初步研究表明，星形胶质细胞分泌蛋白到培养基（星形胶质细胞条件培养基，ACM）中，其通过增加与突触后GABAAR簇共定位的GABA能突触前末端的数量的标准来增加抑制性神经元轴突长度、分支以及突触发生（Elmariah et al.，2005; Hughes等人，2005年，2006年）。这些数据导致的假设，星形胶质细胞分泌的蛋白质影响神经发育过程中抑制回路的形成。本研究将从以下三个方面对这一假说进行验证：（1）通过两个实验来研究星形胶质细胞分泌的蛋白质对抑制性轴突长度、分支和突触发生的影响。(2)我们将继续使用凝胶过滤和质谱鉴定星形胶质细胞分泌的蛋白质，增加抑制轴突长度，分支和突触发生。(3)我们将测试候选分泌蛋白在抑制轴突长度、分支和突触发生中的作用。虽然这些目标是高风险的，但它们也可能具有非常高的影响，因为对影响抑制性神经元的星形胶质细胞分泌蛋白知之甚少。总之，这些实验将扩展我们对神经发育过程中抑制回路如何形成的理解，也可能有助于理解癫痫、自闭症和智力迟钝等发育障碍。公共卫生相关性：我建议研究星形胶质细胞，一种类型的胶质细胞在大脑中，影响抑制性神经元和抑制性突触在发育中的中枢神经系统的形成的信号机制。拟议的实验将有助于了解人类神经系统发育障碍，如癫痫、自闭症和智力迟钝，这些障碍对公共卫生有重大影响。

DESCRIPTION (provided by applicant): I propose to study the mechanisms by which astrocytes modulate inhibitory synaptogenesis in the developing central nervous system. Previous work and preliminary studies in hippocampal neurons in vitro show that astrocytes secrete proteins into the media (astrocyte conditioned media, ACM) that increase inhibitory neuron axon length, branching as well as synaptogenesis, by the criteria of increasing the number of GABAergic presynaptic terminals co-localized with postsynaptic GABAAR clusters (Elmariah et al., 2005; Hughes et al., 2005, 2006). These data lead to the hypothesis that astrocyte secreted proteins affect the formation of inhibitory circuitry during neural development. This hypothesis will be tested in three aims: (1) We will complete our studies to determine how astrocyte secreted proteins affect inhibitory axon length, branching and synaptogenesis in 2 experiments. (2) We will continue to use gel filtration and mass spectroscopy to identify astrocyte secreted proteins that increase inhibitory axon length, branching and synaptogenesis. (3) We will test candidate secreted proteins for their role in inhibitory axon length, branching and synaptogenesis. While these aims are high-risk, they are also potentially of very high impact, as very little is known about astrocyte secreted proteins that affect inhibitory neurons. Taken together, these experiments will extend our understanding of how inhibitory circuitry is formed during neural development, and may also contribute to understanding of disorders of development such as epilepsy, autism and mental retardation. PUBLIC HEALTH RELEVANCE: I propose to study the signaling mechanisms by which astrocytes, a type of glia in the brain, affect inhibitory neurons and the formation of inhibitory synapses in the developing central nervous system. The proposed experiments will contribute to understanding of disorders of human nervous system development such as epilepsy, autism and mental retardation, disorders with a significant public health impact.