Control of synapse formation and maturation by astrocytes

描述（由申请人提供）：突触是神经系统的基本功能单位，但调节其建立的分子和细胞相互作用在很大程度上是未知的。使用纯化的视网膜神经节细胞神经元（RGC）的研究表明，星形胶质细胞分泌的信号，如血小板反应蛋白，强烈诱导兴奋性突触的形成。在我们的初步研究中，我们发现了另一种星形胶质细胞分泌的突触发生蛋白hevin。在纯化的RGC培养物中加入hevin强烈刺激兴奋性突触发生。此外，Hevin基因敲除小鼠的兴奋性突触显著减少，这表明Hevin是体内突触形成和形态成熟所必需的。星形胶质细胞也表达hevin的一种类似物，称为hevin。有趣的是，hevin不是突触发生性的，而是特异性抑制hevin诱导的突触发生。这些数据首次表明，星形胶质细胞不仅通过刺激，而且通过抑制突触发生来调节突触连接。我们的研究结果表明，星形胶质细胞通过调节hevin和hevin的相对水平，可以积极控制发育和成年大脑中突触网络的发育和功能，这种可能性令人兴奋。hevin如何诱导突触形成以及hevin拮抗功能的本质尚不清楚。因此，我们的目标是在这里解开一个新的分子机制，调节突触的发展和维护星形胶质细胞通过hevin/hevin信号。在本申请中，我们将首先检验hevin和hevin调节突触形态（目的1）和体内树突棘突触形成（目的2）的假设。其次，我们将确定hevin/hevin信号传导对体内突触功能的贡献（目的2）。第三，我们将测试的假设，hevin介导的突触通过相互作用与跨突触粘附分子neurexins和neuroligins，而hevin拮抗hevin竞争hevin结合neuroligins（目的3）。这些研究很重要，因为它们将为星形胶质细胞控制突触的形成、维持和功能提供新的见解。这些新的见解将通过推进我们对协调中枢神经系统发育和功能的星形胶质细胞-神经元相互作用的分子和细胞理解产生重大的积极影响。对突触形成以及星形胶质细胞如何参与这一过程的更深入的机械理解将导致开发创新方法来预防或治疗自闭症，抑郁症和成瘾等神经系统疾病。

DESCRIPTION (provided by applicant): Synapses are the fundamental functional units of the nervous system, but the molecular and cellular interactions that regulate their establishment are largely unknown. Studies using purified retinal ganglion cell neurons (RGCs) showed that astrocytes secrete signals such as thrombospondins that strongly induce excitatory synapse formation. In our preliminary studies, we identified another astrocyte-secreted synaptogenic protein, hevin. Addition of hevin to purified RGC cultures robustly stimulates excitatory synaptogenesis. Moreover, Hevin-null mice have significantly less excitatory synapses that present striking structural defects suggesting that hevin is required for the formation and morphological maturation of synapses in vivo. Astrocytes also express a close homolog of hevin called SPARC. Intriguingly, SPARC is not synaptogenic but specifically inhibits hevin-induced synaptogenesis. These data show for the first time that astrocytes regulate synaptic connectivity not only by stimulating, but also by inhibiting synaptogenesis. Our results signify the exciting possibility that astrocytes, through the regulation of relative levels of hevin and SPARC, can actively control the development and function of synaptic networks in the developing and adult brain. How hevin induces synapse formation and the nature of SPARC's antagonistic function are unknown. Therefore, our objective here is to unravel a novel molecular mechanism of regulation of synaptic development and maintenance by astrocytes through hevin/SPARC signaling. In this application, we will first test the hypothesis that hevin and SPARC regulate synaptic morphology (Aim 1) and formation of dendritic spine synapses in vivo (Aim 2). Second, we will determine the contribution of hevin/SPARC signaling to synaptic function in vivo (Aim 2). Third, we will test the hypothesis that hevin mediates synaptogenesis through interactions with the trans-synaptic adhesion molecules neurexins and neuroligins, whereas SPARC antagonizes hevin by competing for hevin-binding to neuroligins (Aim 3). These studies are important since they will provide new insights into the control of formation, maintenance and function of synapses by astrocytes. These new insights will have a significant positive impact by advancing our molecular and cellular understanding of astrocyte-neuron interactions that orchestrate central nervous system development and function. A deeper mechanistic understanding of synapse formation and how astrocytes participate in this process will lead to the development of innovative approaches to prevent or cure neurological disorders such as autism, depression and addiction.