Investigating Sex Differences in Astrocyte-Mediated Synaptic Development

星形胶质细胞对突触连接的调节对中枢神经系统的发育至关重要 神经系统(CNS)，但对男性和男性之间这些过程的差异知之甚少 女性。长期目标是确定涉及星形胶质细胞介导的突触的机制。 为预防或纠正突触回路中断的新疗法提供信息的发展 在男女患者的神经发育疾病中。这样做的主要目标是 应用是研究星形胶质细胞-神经元突触发生的基本差异 在雄性和雌性之间发出信号。中心假设是凝血酶原蛋白(TSP)- 诱导突触发生是男性皮质正常发育所必需的，但不是必不可少的 对于女性，在星形胶质细胞介导的突触发育中建立性别二型性。这个 中心假说将在三个具体目标中得到检验：1)评估星形胶质细胞的性别差异 突触信号转导；2)阐明性别差异的分子机制 TSP诱导的突触发生；3)研究树突棘的性别依赖性调节 突触发育通过TSP受体α2δ-1实现。在第一个目标中，星形胶质细胞条件 来自雄性或雌性大鼠的培养液(含有分泌因子)将被评估其 对来自两性的神经元的突触生成效果。星形细胞雌激素的影响 受体和神经分泌因子对多种星形胶质细胞表达和分泌的影响 突触生成因子也将被确定。对于第二个目的，TSP中的雌激素信号- 经过处理的皮质神经元培养将被操纵来描绘大脑- 衍生神经营养因子(BDNF)、rac1与突触前抑制星形胶质细胞突触生成 发信号。在第三个目标中，将对体内和体外的男性和女性模型进行评估 缺乏TSP突触基因的转基因小鼠树突棘突触的发育 皮质中的受体α2δ-1。这种研究方法是创新的，因为它将严格地 探索星形胶质细胞介导的突触发育不同的新可能性 在男性和女性之间进行调节，并将雌激素确定为显著的调节因素 在这个过程中。在本申请中提出的研究具有重要意义，因为它将提供 旨在阐明新机制的日益强大的实验设计的基础 两性的突触发生和星形胶质细胞/神经元的串扰。调查性别差异 在星形胶质细胞中，信号传递将扩大我们对两种男性突触网络形成的理解 以及女性，以便产生识别、预防或纠正异常的创新策略 自闭症和精神分裂症等发育性中枢神经系统障碍中的突触连接。

Regulation of synaptic connectivity by astrocytes is critical for development of the central nervous system (CNS), yet little is known about how these processes differ between males and females. The long-term goal is to identify mechanisms involved in astrocyte-mediated synaptic development in order to inform novel therapies to prevent or correct disrupted synaptic circuitry in neurodevelopmental diseases in patients of both sexes. The primary objective of this application is to investigate basic fundamental differences in astrocyte-neuron synaptogenic signaling between males and females. The central hypothesis is that thrombospondin (TSP)- induced synaptogenesis is required for proper cortical development of males but less essential for females, establishing sexual dimorphism in astrocyte-mediated synaptic development. The central hypothesis will be tested in three specific aims: 1) Evaluate sex differences in astrocyte synaptogenic signaling; 2) Elucidate the molecular mechanism underlying sex differences in TSP-induced synaptogenesis; and 3) Investigate sex-dependent regulation of dendritic spine and synapse development by the TSP receptor, α2δ-1. In the first aim, astrocyte-conditioned media (containing secreted factors) from either male or female rats will be evaluated for their synaptogenic efficacy on neurons derived from either sex. The impact of astrocytic estrogen receptors as well as neuron-secreted factors on expression and secretion of various astrocytic synaptogenic factors will also be determined. For the second aim, estrogen signaling in TSP- treated cortical neuron cultures will be manipulated to delineate the contributions of brain- derived neurotrophic factor (BDNF), Rac1, and presynaptic muting on astrocyte synaptogenic signaling. In the third aim, male and female in vivo and ex vivo models will be assessed for dendritic spine synaptic development in a transgenic mouse line lacking the TSP synaptogenic receptor, α2δ-1, in the cortex. This research approach is innovative because it will rigorously explore the novel possibility that astrocyte-mediated synaptic development is differentially regulated between males and females and identify estrogen as a prominent regulatory element in this process. The research proposed in this application is significant because it will provide the basis for increasingly robust experimental designs intended to elucidate novel mechanisms of synaptogenesis and astrocyte/neuronal crosstalk in both sexes. Investigating sex differences in astrocyte signaling will expand our understanding of synaptic network formation in both males and females in order to generate innovative strategies to identify, prevent, or correct aberrant synaptic connectivity in developmental CNS disorders such as autism and schizophrenia.