Astrocyte bioenergetics in brain development, network activity, and cognition

星形胶质细胞生物能量学在大脑发育、网络活动和认知中的作用

• 批准号: 9761579
• 负责人: Mikhail V Pletnikov
• 金额: $ 57.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761579
• 关键词: 22q; 22q11; Adolescence; Adolescent; Adult; Affect; Applications Grants; Area; Astrocytes; Behavior; Behavioral Symptoms; Bioenergetics; Bipolar Disorder; Blood Vessels; Brain; Brain region; Cells; Chronic; Cognition; Cognition Disorders; Cognitive deficits; Complex; Consensus; Copy Number Polymorphism; Data; Development; Disease; Drug or chemical Tissue Distribution; Energy Metabolism; Energy Supply; Genes; Genetic; Genetic Risk; Genetic Transcription; Genomics; Glutamate Metabolism Pathway; Glutamates; Homeostasis; Human; Image; Impaired cognition; In Vitro; Knock-out; Knockout Mice; Lead; Learning; Mental disorders; Metabolic; Metabolic Pathway; Mitochondria; Molecular; Moods; Morphology; Mus; Mutant Strains Mice; Names; Neurobehavioral Manifestations; Neuronal Dysfunction; Neurons; Orthologous Gene; Parvalbumins; Pathway interactions; Patients; Physiology; Prefrontal Cortex; Process; Prosencephalon; Proteins; Proteomics; Psyche structure; Reporting; Research; Respiration; Role; Sampling; Schizophrenia; Tertiary Protein Structure; Testing; Time; Transcriptional Regulation; Variant; Work; brain cell; cognitive function; depressive symptoms; early onset; experimental study; genetic risk factor; genetic variant; genome wide association study; in vivo; interest; mitochondrial dysfunction; molecular pathology; new therapeutic target; postnatal; psychogenetics; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

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.

项目总结