Astrocyte bioenergetics in brain development, network activity, and cognition

项目摘要 星形胶质细胞能量供应的缺陷可能导致神经元功能和认知功能异常。 与严重精神障碍方面相一致的损害。精神分裂症和双相情感障碍患者 这些疾病表现出线粒体功能障碍和代谢改变的迹象。这些机制 代谢变化仍不清楚。最近的GWA研究表明， 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中异常的线粒体呼吸和谷氨酸代谢 神经元PAS结构域蛋白3（NPAS 3）是由高渗透性星形胶质细胞遗传风险因子产生的 其转录靶基因22q.11 CNV基因SLC 2518 A将影响CNV细胞的形态和生理。 脆弱的前额叶皮层小白蛋白阳性（PV+）神经元在一定时间内损害认知功能， 大脑区域依赖性的方式。 我们假设星形胶质细胞中这种代谢途径的异常将导致慢性的 谷氨酸分泌增加，反过来，将以时间依赖性方式影响神经元和认知功能， 和脑回路相关的方式。 特异性目的1将确定NPAS 3转录调控的分子机制， 星形胶质细胞中的SLC 25 A18。 特异性目的2将确定NPAS 3-SLC 25 A18相互作用在线粒体呼吸中的作用， 星形胶质细胞的谷氨酸代谢。 具体目标3将确定星形胶质细胞中代谢改变对时间和大脑的贡献。 回路依赖性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，导致异常的能量和谷氨酸稳态， 皮质PV+神经元和认知障碍。

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.