Astrocyte bioenergetics in brain development, network activity, and cognition

项目摘要 星形胶质细胞能量供应不足可能导致神经元功能和认知功能异常 损害与主要精神障碍的某些方面相一致。精神分裂症和躁郁症患者 紊乱表现为线粒体功能障碍和代谢改变的迹象。它们的作用机制 新陈代谢的变化仍然不清楚。最近的GWA研究表明，几个遗传风险因素与 星形胶质细胞中的线粒体生物能量学。 我们将研究星形胶质细胞线粒体呼吸和谷氨酸代谢异常 由高渗透性星形胶质细胞遗传风险因子神经元PAS结构域蛋白3(NPAS3)产生 它的转录靶点是22q.11 CNV基因SLC2518A，它将影响细胞的形态和生理。 易受攻击的前额叶皮质小白蛋白阳性神经元在一定时间内损害认知功能 脑区依赖的方式。 我们假设星形胶质细胞代谢途径的异常将导致慢性 谷氨酸分泌增加，这反过来将影响神经元和认知功能的时间依赖 和脑回路相关的方式。 特异性靶点1将确定NPAS3转录调控的分子机制 SLC25A18在星形胶质细胞中表达。 特异性目标2将确定NPAS3-SLC25A18相互作用在线粒体呼吸和 星形胶质细胞中的谷氨酸代谢。 具体目标3将确定星形胶质细胞的代谢变化对时间和大脑的贡献 电路依赖型神经元和认知功能障碍。 我们的研究将促进我们对遗传风险因素如何影响关键代谢的理解 星形胶质细胞中的通路，导致能量和谷氨酸稳态异常，抑制活性不足 大脑皮层PV神经元与认知障碍。

Project Summary Deficits in astrocyte energy supply could lead to abnormal neuronal function and cognitive impairment consistent with aspects of major psychiatric disorders. Patients with schizophrenia and bipolar disorder demonstrate signs of mitochondria dysfunction and metabolic alterations. The mechanisms of these metabolic changes remain obscure. Recent GWA studies have implicated several genetic risk factors in mitochondria bioenergetics in astrocytes. We will study how abnormal mitochondria respiration and glutamate metabolism in astrocytes produced by the highly penetrant astrocyte genetic risk factors, Neuronal PAS domain protein 3 (NPAS3) and its transcriptional target, a 22q.11 CNV gene, SLC2518A, will affect the morphology and physiology of vulnerable parvalbumin-positive (PV+) neurons of prefrontal cortex to impair cognitive function in a time and brain region-dependent manner. We hypothesize that abnormalities in this metabolic pathway in astrocytes will lead to a chronic increase in glutamate secretion that, in turn, will affect neuronal and cognitive functions in a time-dependent and brain circuit-related manner. Specific Aim 1 will determine the molecular mechanisms of NPAS3 transcriptional regulation of SLC25A18 in astrocytes. Specific Aim 2 will determine the role of NPAS3-SLC25A18 interplay in mitochondria respiration and glutamate metabolism in astrocytes. Specific Aim 3 will determine the contributions of metabolic alterations in astrocytes to time- and brain circuit-dependent neuronal and cognitive dysfunction. Our studies will advance our understanding of how genetic risks factors influence the key metabolic pathways in astrocytes, leading to abnormal energy and glutamate homeostasis, deficient inhibitory activity of cortical PV+ neurons and cognitive impairment.