The role of astrocytes in inhibitory synaptogenesis

描述(申请人提供)：CMS突触的组装是一个复杂和动态的过程，需要突触前、突触后神经元和周围神经胶质细胞之间的信号协调交换。星形胶质细胞是胶质细胞的一种，已被证明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和接触。然而，星形胶质细胞在抑制突触形成和功能中所起的作用还没有得到很好的研究。这项建议的目的是研究星形胶质细胞在发育中的神经系统中抑制性突触发生中的作用。Balice-Gordon实验室之前的工作和我在海马神经元体外的初步研究表明，星形胶质细胞向介质(星形胶质细胞条件培养液，ACM)释放可溶信号，通过增加与突触后GABAAR簇共存的GABA能突触前终末的数量来增加抑制性神经元轴突的延长、分支以及突触发生(Elmariah et a I.，2005；Hughes等人，2005)。我的初步研究还表明，神经元与星形胶质细胞的接触，而不是ACM，增加了功能性GABA能突触的数量。这导致了一种假设，即在神经发育过程中，来自星形胶质细胞的分泌和接触信号不同地调节抑制性突触的形成和功能。为了验证这一假设，我将：(1)在一系列实验中确定星形胶质细胞可溶信号如何影响抑制性轴突生长、分支和突触形成。(2)探讨神经元-星形胶质细胞接触在抑制性突触功能发育中的作用。(3)鉴定星形胶质细胞释放的促进抑制性轴突生长、分支和突触形成的可溶性信号。综上所述，这些实验将扩大我们对抑制性突触在神经发育过程中是如何形成的理解。这些研究的结果将扩大我们对神经元-胶质细胞信号如何调节突触形成和功能的理解，并为确定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基础，未来可能会为癫痫、自闭症和智力低下等发育障碍的治疗干预提供途径，在这些疾病中，突触形成和/或功能异常或降低。

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.