Abstract
Schizophrenia is one of the most complex and debilitating brain diseases. Patients with schizophrenia may present various clinical manifestations that have been categorized into positive symptoms , negative symptoms, and cognitive deficits. In relation to these complex clinical manifestations, multiple hypotheses have been proposed to understand the pathogenesis of schizophrenia, such as the so-called dopamine (DA) hypothesis, mitochondrion hypothesis, oligodendrocyte (OL) hypothesis, etc. The concurrent existence of multiple hypotheses about one brain disease suggests a possible common neurobiological mechanism linking some of these hypotheses. This possible neurobiological mechanism has been demonstrated in this study with animal models of schizophrenia, cultured OLs, and neuron-OL co-cultures. Adolescent C57BL/6 mice given tolcapone (TOL) for two weeks showed DA elevation in prefrontal cortex (PFC), functional impairment of mitochondria in brain cells, and hypomyelination in PFC, hippocampus, and caudate putamen (CPu) in a dose-dependent manner, in addition to schizophrenia-related behaviors. The catechol-O-methyltransferase (COMT) gene knock-out (COMT-ko) mice presented dopaminergic dysfunctions in PFC and CPu, functional deficit of mitochondria, mature OL decrease, and hypomyelination in the same brain regions as those in TOL-treated mice. In cultured OLs, DA inhibited the cell development in a concentration-dependent manner while impairing mitochondrial functions. These effects of DA on cultured cells were ameliorated by the antioxidant N-acetyl-L-cysteine (NAC) and trans-2-phenylcyclopropy (TCP), an inhibitor of mitochondrial monoamine oxidases (MAOs). Moreover, DA inhibited axonal myelination in neuron-OL co-cultures while impairing mitochondrial functions. These data demonstrate the pivotal roles of mitochondria in linking DA catabolism to axonal myelination in the brain and provide a novel insight into the pathogenesis and therapeutic strategy for schizophrenia.