MITOCHONDRIAL DYSFUNCTION PLAYS A ROLE IN IMPAIRED NEURONAL DIFFERENTIATION IN SCHIZOPHRENIA

Abstract

Schizophrenia (SZ) is conceptualized as a neurodevelopmental disorder, involving dysfunction of dopaminergic and glutamatergic systems as well as of mitochondria. Among the major obstacles in studying pathological processes in SZ are the inaccessibility of the brain and inability to study brain processes prior to the onset of this disorder. Animal models of the disease can shed light on possible developmental aberration in the disease. An additional attractive experimental tool to study neurodevelopmental impairments together with mitochondrial dysfunction in SZ, is differentiation of induced pluripotent stem cells (iPSC) into neurons.iPSC from SZ patients and healthy controls were reprogrammed from hair follicle keratinocytes and differentiated into dopaminergic and glutamatergic neurons. Mitochondria were assessed by analyzing mitochondrial membrane potential, network dynamics and apoptosis markers. The effect of transferring isolated active normal mitochondria (IAN-MIT) into SZ- iPSCs was studied. Furthermore, mitochondrial complex I subunits expression was followed in brains of neonatal ventral hippocampal (nVH) damage rat model of SZ.SZ-derived dopaminergic cells showed severely impaired ability to differentiate, whereas glutamatergic cells were unable to maturate. Mitochondrial complex I driven respiration was impaired in SZ-derived keratinocytes and iPSC along with perturbations in mitochondrial membrane potential and in mitochondrial network in neurons. However, amending mitochondrial function by IAN-MIT transfer improved differentiation of SZ-iPSC derived glutamatergic neurons. In prefrontal cortex, but not the cingulate cortex, of nVH damage rat model of SZ we observed a significant prepubertal increase and postpubertal decrease in mitochondrial complex I subunits. No such change was observed in neonatal exposure to hypoxia rat model.Our study shows perturbations in neural differentiation and mitochondrial function, which are interconnected and of relevance to early neurodevelopmental processes in SZ.