Investigating Sex Differences in Astrocyte-Mediated Synaptic Development

研究星形胶质细胞介导的突触发育的性别差异

• 批准号: 10203369
• 负责人: William Christopher Risher
• 金额: $ 44.4万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10203369
• 关键词: Affect; Aftercare; Astrocytes; Binding; Brain; Brain-Derived Neurotrophic Factor; CD36 Antigens; Calcium Channel; Central Nervous System Diseases; Data; Dendritic Spines; Development; Developmental Process; Disease; Estrogen Receptors; Estrogens; Experimental Designs; Female; Future; Goals; Gonadal Steroid Hormones; Image; Immunohistochemistry; Incidence; Knock-out; Knowledge; Letrozole; Mediating; Mission; Modeling; Molecular; Mus; Neuraxis; Neurodevelopmental Disorder; Neurologic Dysfunctions; Neurons; Pathway interactions; Patients; Pattern; Pharmacology; Prevention; Process; Production; Prosencephalon; Proteins; Public Health; Rattus; Regulation; Regulatory Element; Research; Role; Schizophrenia; Sex Bias; Sex Differences; Signal Transduction; Slice; Surface; Synapses; Testing; Thrombospondins; Time; Transgenic Mice; United States National Institutes of Health; Visual Cortex; Work; area striata; autism spectrum disorder; hormonal signals; improved; in vivo; innovation; insight; male; neural circuit; novel; novel therapeutics; presynaptic; prevent; receptor; sex; sexual dimorphism; synaptogenesis

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.

星形胶质细胞对突触连接的调节对于中枢神经系统的发育至关重要。 神经系统（CNS），但很少有人知道这些过程在男性和女性之间有何不同。 女性长期的目标是确定星形胶质细胞介导的突触传递的机制。 开发，以告知新的疗法，以防止或纠正中断的突触电路 在神经发育疾病中的作用。这项工作的主要目的是 应用是研究星形胶质细胞-神经元突触发生的基本差异， 雄性和雌性之间的信号核心假设是血小板反应蛋白（TSP）- 诱导的突触发生是雄性皮质正常发育所必需的， 对于女性，在星形胶质细胞介导的突触发育中建立性二型性。的 中心假设将在三个具体目标中进行检验：1）评估星形胶质细胞的性别差异 突触发生信号; 2）阐明性别差异的分子机制， TSP诱导的突触发生;和3）研究树突棘的性别依赖性调节 和突触发育的TSP受体，α2δ-1。在第一个目标中， 将评价来自雄性或雌性大鼠的培养基（含有分泌因子）的 对来自任一性别的神经元的突触发生功效。星形胶质细胞雌激素的影响 受体以及神经分泌因子对各种星形胶质细胞表达和分泌的影响。 还将确定突触发生因子。对于第二个目标，TSP中的雌激素信号传导- 处理的皮层神经元培养物将被操作以描绘脑- 脑源性神经营养因子（BDNF）、Rac 1和突触前突变对星形胶质细胞突触形成的影响 发信号。在第三个目标中，将评估雄性和雌性体内和离体模型的 缺乏TSP突触形成基因的转基因小鼠树突棘突触的发育 受体α2δ-1。这种研究方法是创新的，因为它将严格 探索星形胶质细胞介导的突触发育差异的新可能性 调节之间的男性和女性，并确定雌激素作为一个突出的调节因素 在这个过程中。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稳健的实验设计的基础 突触发生和星形胶质细胞/神经元串扰的性别。调查性别差异 在星形胶质细胞信号传导中的作用将扩大我们对雄性和雌性中突触网络形成的理解， 和女性，以产生创新的战略，以确定，预防，或纠正异常 突触连接在发育中枢神经系统疾病，如自闭症和精神分裂症。