Epigenetic Alterations of the Developing Brain in Animal Models of Schizophrenia

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DESCRIPTION (provided by applicant): Epigenetic regulation of gene transcription, specifically when related to changes in DNA-methylation patterns (methylome), is a plausible mechanism underlying long-term environmental contributions to neuropsychiatric disorders. For example, pharmacological or environmentally-induced methylome alterations may lead to the silencing or aberrant activation of genes involved in the postnatal maturational process of brain circuitry, leading to functional and behavioral alterations appearing when the system reaches maturity. We and others have shown that activation of oxidative stress mechanisms during the period of maturation of brain inhibitory neurons leads to permanent neurochemical changes and schizophrenia-like behavior when animals reach adulthood. However, the mechanisms by which oxidative stress leads to disruption of the brain maturational process are unknown. Oxidative stress and inflammatory mediators are known to lead to epigenetic alterations in cancer, and activation of such mechanisms may have profound consequence during critical periods of brain maturation. Our preliminary findings suggest that activation of oxidative stress mechanisms during early life may produce epigenomic modifications, due to methylome changes, that affect neurodevelopment and thus may underlie the origins of the schizophrenia syndrome and possibly other mental disorders. We will test this hypothesis during postnatal development of frontal cortex of mice subjected to two developmental manipulations, known to lead to schizophrenia-like behavioral and neurochemical alterations in early adulthood. Three specific aims will be developed: Aim 1 will use MethylC-Seq to produce genome-wide, single-base resolution maps of methylated cytosines (methylome) during mouse postnatal brain-development at the tissue and brain cell-type levels, and determine the consequences of methylation changes at the transcriptional level by RNA-Seq (transcriptome). Aim 2 will determine the methylome and transcriptome changes induced by two non-overlapping neurodevelopmental models of schizophrenia in the two major neuronal populations in frontal cortex, and will produce transcriptome data for all inhibitory subtypes at two developmental time points. Aim 3 will determine whether treatment-induced methylome and transcriptome changes can be observed in peripheral blood cells (neutrophils). Health Impact: The proposed studies will produce a complete map of the mouse frontal cortex methylome, at the tissue and cell-type level, during the period of postnatal development until adulthood. Moreover, it will delineate the methylome changes and transcriptional consequences produced by two developmental manipulations that lead to schizophrenia-like behavior in adulthood, at the neuronal and peripheral tissue level. By making the data publically available, it will serve as a standard reference for methylome and transcriptome databases that can be consulted in relation to neuropsychiatric disorders with known and unknown developmental origins. PUBLIC HEALTH RELEVANCE: Epigenetic regulation of gene transcription, specifically DNA methylation, is a potential mechanism by which environmental contributions can lead to the modulation of brain development and function. Thus, genetic, environmental, or pharmacologically driven changes in normal patterns of DNA methylation may be at the origin of neuropsychiatric disorders. Our studies will produce genome-wide single-base maps, at the tissue and cell-type level, of the brain-methylome changes during postnatal brain development, and will provide detailed maps of how these changes are affected by two developmental manipulations that lead to schizophrenia-like behavior in adulthood.