Schizophrenia (SZ) has been characterized as a disconnectivity syndrome where communication between different neurons, brain circuits and brain regions is disrupted leading to failures of appropriate/coherent information processing. In order to maintain functional processing and rapid neurotransmission at all levels of the nervous system, neurons require adequate myelination of their axons. The success of myelination depends on coordinated interplay of the extrinsic and intrinsic signals that mediate recruitment, differentiation and migration of oligodendrocyte precursor cells (OPC). In prior research, now replicated by many groups, we showed that SZ was characterized by significant reductions in the expression of multiple myelin and oligodendrocyte (OLG) associated genes and proteins. We also showed that the myelin related expression deficits in SZ are associated with the failure of execution of the normal cell-cycle arrest in postmitotic OLGs that may adversely affects myelin function. Genomic translocation on chromosome 1q42 associated with SZ that interrupts the disrupted-In-schizophrenia-1 gene (DISC1) may produce truncated and nonfunctional DISC1 protein. Our recent studies in transgenic mice with neuron exclusive expression of truncated human DISC1 (DhDISC1) have re- veal strong dysregulation of markers of OPC and OLGs along with cell cycle genes throughout development and adulthood suggesting that DhDISC1 can exert a major influence on proliferation and migration of oligoden drocyte precursors, their differentiation into OLGs and ultimately OLG function. The current proposal aims to gain deeper understanding into the mechanisms that contribute to the OLG dysfunction in SZ.
These aims i nclude: (1) assessing effects of neuron-exclusive DhDISC1 on migration, proliferation and differentiation of glial progenitor cells in transgenic mice and determining developmental population of glial progenitor cells targeted by DhDISC1 expression;(2) examining molecular pathways (elicited by NRG1, IGF1 and Wnt) that may mediate the effect of DhDISC1 on migration, proliferation and differentiation of OPC by studying gene/protein expression and phosphorylation of critical effectors of the pathways;(3) examining regional changes in expression of proteins connecting functionally defective DISC1 to OLG-related dysfunction in SZ in human postmortem brains and determine their disease relevance. Our approach is to understand better OLG development and function in SZ through an iterative process of identifying neurobiological abnormalities in SZ, using transgenic animal models to uncover the mechanisms responsible and validating the findings from animal models against real-world outcomes in the human brain and guide to possible preventive or interventional strategies with direct public health impact.
The hypothesis that human mutant Disrupted-in schizophrenia 1 protein involved in the dysregulation of migration and differentiation of oligodendrocytes underlie aspects of the pathophysiology of schizophrenia brings a relatively uncommon conceptual and mechanistic approach to the study of the neurobiology of the disease. Our planed approach will generate valuable information on neuron-glia interactions during development and their contribution to the regional cortical myelin deficit with relevance to the pathogenesis of schizophrenia and guide to possible preventive or interventional strategies with direct public health impact.