Microarrays and qPCR studies have identified significant deficits in the expression of myelin and oligodendrocyte-related (OMR) genes in SZ. These studies, which have been consistently replicated in multiple cohorts of persons with SZ, have shown that deficits in the expression of the OMR genes occur in the context of the abnormal expression of multiple cell cycle related (CCR) genes and proteins. Although the preliminary results presented implicate cell cycle abnormalities in oligodendrocytes (OLG), increasing evidence suggests that some of the same CCR genes may be involved in mechanisms of neuronal dysfunction also. Therefore, the proposed studies will investigate neuron and oligodendrocyte enriched cell populations separately using laser capture microdissection (LCM) in postmortem brain specimens from persons with SZ and controls. We will test the overarching hypothesis that the myelin associated gene and protein expression deficits in SZ are due in part to a failure of execution of the normal cell-cycle arrest or suppression program by postmitotic oligodendrocytes. More specifically and based on our preliminary studies we hypothesize that terminally differentiated oligodendrocytes reenter the cell cycle and begin executing a pathological program that adversely affects the expression of OMR genes and myelin function. Based on preliminary data and published reports, this overarching hypothesis will be tested at multiple levels. 1) We will test the hypothesis that abnormalities in the expression of selected cell cycle genes and proteins will be qualitatively similar to, i.e., correlated with, abnormalities in OMR genes and proteins in multiple brain regions. 2) We will use LCM to selectively enrich samples for oligodendrocytes and neurons to test the hypothesis that the CCR gene expression abnormalities observed in mixed cell brain homogenates of persons with SZ are attributable to CCR gene expression disturbances in oligodendrocytes and not in neurons. 3) We will use LCM to selectively enrich samples for oligodendrocytes and neurons to test the mechanistic hypothesis that the expression of genes associated with one or more mitogens and/or their receptors (e.g., FGF and FGF receptors) will coincide with the abnormal expression of OMR genes in different brain regions of persons with SZ. 4) We will use an identical cell-type enrichment protocol and mouse model systems to test the specific hypothesis that the exogenous manipulation of the brain levels of a well-described oligodendroglial mitogen, bFGF, will dysregulate the cell cycle of oligodendrocytes and will induce OMR gene expression deficits that are similar to those observed in SZ. The completion of the proposed studies will provide a better mechanistic understanding of the neurobiological processes responsible for the abnormal expression of multiple myelin-associated genes in schizophrenia and the biological basis of the disconnectivity syndrome hypothesis.
Schizophrenia continues to be a significant public health problem. The NIMH and the Global Burden of Disease estimate that schizophrenia affects 1.1% of the US population aged 18 and over each year. Although significant progress has been made in treatment strategies that diminish some of the symptoms of the disease, the neurobiological bases of the disease continue to be elusive. The research program proposed here aims to identify at least some of the neurobiological mechanisms that may be involved in the disease process. Specifically, we seek to determine whether cells in the brain that promote efficient communication between neurons are fundamentally affected by schizophrenia. We predict that the identification of the specific cell types and biological processes affected by the disease will enable the design and development of rational and evidence based therapeutic approaches.
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