The role of astrocytes in inhibitory synaptogenesis

描述（由申请人提供）：CMS突触的组装是一个复杂的动态过程，需要突触前和突触后神经元与周围神经胶质之间协调的信号交换。星形胶质细胞是神经胶质细胞的一种，它可以增加兴奋性突触的形成和功能，部分是通过释放可溶性因子以及接触。然而，星形胶质细胞在抑制性突触形成和功能中的作用还没有得到很好的研究。本研究的目的是研究星形胶质细胞在发育中的神经系统中抑制突触发生的作用。来自Balice-Gordon实验室的先前工作和我在体外海马神经元中的初步研究表明，星形胶质细胞释放可溶性信号到培养基（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伸长、分支以及突触发生（Elmariah et a I.，2005; Hughes等人，2005年）。我的初步研究还表明，神经元与星形胶质细胞接触，而不是ACM，增加功能性GABA能突触的数量。这导致的假设，分泌和接触信号的星形胶质细胞差异介导的形成和功能的抑制性突触在神经发育。为了验证这一假设，我将：（1）通过一系列实验确定星形胶质细胞可溶性信号如何影响抑制性轴突生长、分支和突触发生。(2)检查神经元-星形胶质细胞接触在抑制性突触功能发展中的作用。(3)识别星形胶质细胞释放的可溶性信号，增加抑制轴突生长，分支和突触发生。总之，这些实验将扩展我们对神经发育过程中抑制性突触如何形成的理解。这些研究的结果将扩展我们对神经胶质细胞信号传导如何调节突触形成和功能的理解，并为定义潜在的细胞和分子机制奠定基础。了解这些机制将提供一个知识的基础，可能在未来，建议治疗干预的发展障碍，如癫痫，自闭症和精神发育迟滞，其中突触的形成和/或功能异常或减少的途径。

DESCRIPTION (provided by applicant): The assembly of CMS synapses is a complex and dynamic process, requiring the coordinated exchange of signals between pre- and postsynaptic neurons and surrounding glia. Astrocytes, one type of glia, have been shown to increase the formation and function of excitatory synapses, in part by releasing soluble factors as well as by contact. However/the role that astrocytes play in inhibitory synapse formation and function has not been well studied. It is the goal of this proposal to examine the role of astrocytes in inhibitory synaptogenesis in the developing nervous system. Previous work from the Balice-Gordon lab and my preliminary studies in hippocampal neurons in vitro suggest that astrocytes release soluble signals into the media (astrocyte conditioned media, ACM) that increase inhibitory neuron axon elongation, branching as well as synaptogenesis, by the criteria of increasing the number of GABAergic presynaptic terminals co-localized with postsynaptic GABAAR clusters (Elmariah et a I.", 2005; Hughes et al., 2005). My preliminary studies also suggest that neuronal contact with astrocytes, but not ACM, increase the number of functional GABAergic synapses. This leads to the hypothesis that secreted and contact signals from astrocytes differentially mediate the formation and function of inhibitory synapses during neural development. To test this hypothesis, I will: (1) Determine how astrocyte soluble signals affect inhibitory axon outgrowth, branching and synaptogenesis in a series of experiments. (2) Examine the role of neuron- astrocyte contact in the development of inhibitory synapse function. (3) Identify soluble signals released by astrocytes that increase inhibitory axon outgrowth, branching and synaptogenesis. Taken together, these experiments will extend our understanding of how inhibitory synapses are formed during neural development. The results of these studies will extend our understanding of how neuron-glia signaling modulates synapse formation and function, and set the stage for defining the underlying cellular and molecular mechanisms. Understanding these mechanisms will provide a foundation of knowledge that may, in the future, suggest avenues for therapeutic intervention for disorders of development such as epilepsy, autism and mental retardation, in which synapse formation and/or function are aberrant or reduced.