Dysfunction of the prefrontal cortex (PFC) is thought to play a key role in the neurobiology of schizophrenia. In particular, the deficit syndrome which includes a subset of negative symptoms such as anhedonia, amotivation, apathy and poverty of thought content, is thought to result from PFC malfunction. The neurobiology of PFC dysfunction in schizophrenia remains enigmatic, but it is now thought that, among other factors, functional hypometabolism and deficits in NMDA receptor-mediated signaling play a crucial role. It is thought that dysregulated gene expression in PFC and other brain regions of schizophrenics contributes to these defects, but the molecular pathology of transcriptional dysregulation in schizophrenia, including the underlying genetic and epigenetic mechanisms, remain unclear. In eukaryotes, including humans, changes in gene expression are typically accompanied by dynamic alterations in chromatin structure and function. Epigenetic control of gene expression, in particular, is mediated through a combinatorial set of covalent modifications at N-terminal residues of the core histones. Our central goals are 1) to find out, if in human brain, region-specific expression of NMDA receptor subunits is regulated through differential histone methylation and acetylation in chromatin surrounding 5' regulatory sequences of NMDA receptor subunit genes; and 2) to determine if, in PFC of schizophrenics, decreased expression of metabolic or NMDA receptor signaling-related mRNAs is accompanied by a deficit in open chromatin-associated histone methylation at the corresponding genes; and 3) to determine if chronic treatment with antipsychotic drugs induces epigenetic chromatin modifications at defined genomic regions in cerebral cortex. Our experiments will focus on human prefrontal and cerebellar cortex and will rely on a modified chromatin immunoprecipitation technique specifically designed for postmortem tissue. It is expected that this novel approach will provide (i) a clear picture on covalent chromatin imprints regulating gene expression in human brain and (ii) clarify if histone modifications as epigenetic regulators of gene expression contribute to transcriptional dysregulation affecting metabolism and NMDA receptor signaling in PFC of schizophrenics.
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