Epigenetic mechanisms enable biological systems to respond and adapt to environmental stimuli by altering gene expression. Alternatively, environmental influences can evoke undesired and persistent epigenetic effects. These maladaptive events that may increase susceptibility to nervous system deficits. Recently, epigenetic mechanisms have been implicated in chronic neuronal dysfunction underlying some psychiatric and neurological diseases. CBP (CREB Binding Protein) acetyltransferase is a primary regulator of epigenetic expression of neuronal genes. The CBP gene is critical for maintaining neural network homeostasis. CBP haploinsufficiency leads to mental retardation. My previous work has demonstrated that CBP acetyltransferase function is critical for controlling temporal neuronal network dynamics in signal processing and NMDA receptor-dependent memory consolidation. Conversely NMDA receptor hypofunction has been strongly implicated in schizophrenia, since NMDA receptor antagonist, such as phenylcyclidine (PCP), replicate schizophrenic symptoms. The primary hypothesis of this work is that an impairment in CBP HAT activity will affect the response to sub-chronic treatment with PCP. The specific clinical question is whether we can identify the epigenetic mechanisms involved in the etiology of progressive schizophrenia. We will establish a novel model combining pharmacological and genetic manipulations to study mechanisms controlling histone modifications. We will identify gene promoter-specific epigenetic misregulation associated with brain diseases involving dysfunctional or uncoordinated synaptic transmission. I propose two specific aims. In Specific Aim 1, the response of mutant mice expressing a dominant negative inhibitor of CBP acetyltransferase activity to chronic treatment with PCP will be determined. In Specific Aim 2, the capability of histone deacetylase inhibitors to rescue phenotypes obtained in the CBP{HAT-} mutant mice treated with PCP will be examined. The proposed research will set the stage for the investigation of systems-level mechanisms contributing to schizophrenia-like symptoms. These experiments will provide insights into the molecular mechanisms underlying cognitive dysfunction and into the pathological processes related to schizophrenia. These findings could lead to treatments that prevent development of psychosis. Thus, this research is directly relevant to the mission of the NIH. PUBLIC HEALTH RELEVANCE: Schizophrenia is believed to be caused by a combination of inherited genes and environmental factors. In this project, we seek to identify the epigenetic mechanisms involved in the development of schizophrenia. Our findings will provide a novel model of schizophrenia that can be used to study the molecular mechanisms underlying cognitive dysfunction and for testing drugs that directly target epigenetic mechanisms underlying the pathology of psychosis.