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.
The grant application proposes to determine the role of psychiatric genetic risk factors, Neuronal PAS domain protein 3 and SLC25A18, in metabolic alterations observed in major mental diseases. We hope that our proposal will uncover new therapeutic targets to treat metabolic abnormalities in patients to ameliorate their behavioral and cognitive symptoms.
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