Edward Korzus - US grants

This proposal focuses on our efforts to understand molecular mechanisms regulating memory formation. It has been previously shown that cAMP response element binding protein (CREB)-mediated transcription is required in long-term plasticity and this phenomenon is conserved from mollusks to mammals although the presence of multiple CREB forms in mammals complicates interpretation of results obtained from study of CREB mutant mice. The proposed research will involve study of transcription- dependent synaptic plasticity which underlies learning and memory processes. The generated mutant mice will allow for genetic control of CREB-dependent gene expression in hippocampal neurons, and study the molecular and cellular mechanisms of the transition from short- to long-term memory. Mutant mice will be challenged in several learning and memory paradigms which are known to be dependent on the integrity of hippocampus. A newly created mouse model will provide the unique approach to study memory consolidation at molecular, cellular and cognitive level.

DESCRIPTION (provided by applicant): 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.

? DESCRIPTION (provided by applicant): The neural circuits that keep memories distinct and resistant to confusion present a complex set of unknown mechanisms critical both to basic understanding and human well-being. Failure to discriminate between aversive and harmless stimuli due to the similarity of external cues present during trauma in humans can lead to the intrusive recollection of aversive memories. Overgeneralized fear evoked by trauma reminders is typical of anxiety disorders including posttraumatic stress disorder (PTSD), believed to be triggered by cues resembling traumatic experience despite a currently secure environment. Our long-term goal is to characterize mechanisms for fear memory accuracy versus generality and how these translate into control of neural circuits, behavior, and mental disorders. The central hypothesis of this project, based on our preliminary data and a large body of previous work, is that fear memory accuracy is attained via a medial prefrontal cortex (mPFC) dependent mechanism involving reduction of fear responses to harmless nonreinforced stimuli. Fear extinction appears to rely on prefrontal circuitry through a process by which initially generalized fear memories are selectively reduced by responses to non-reinforced (harmless) stimuli, possibly consolidating selective memories through interactions with the amygdala and/or the hippocampal system. The first Aim of this project is to investigate the role of signaling in the medial prefrontal cortex in fear discrimination learning. Using genetic tagging of neurons activated in response to external stimuli, we will evaluate changes in neuronal activity patterns in the mPFC, amygdala and hippocampus. The investigation will include evaluation of the capability of histone deacetylase inhibitors to rescue induced deficits in discriminative fear learning. The clinical rationale for the proposed research is that understanding the control of acetyltransferase function over discriminative fear learning will present a specific mechanism and target for known drugs which, in combination with cognitive therapy, can reverse a phenotype reminiscent of PTSD. The second Aim investigates the role of prefrontal long-range contacts in fear discrimination. Manipulation of the prefrontal projection to amygdala, using circuit-specific regulation of neural activity and by targeting neural biomarkers of memory consolidation, will precede electrophysiological assessment of circuit properties and rescue experiments. Designed to gain insight into information processing, coding and gating relevant to discriminatory fear learning, these experiments also will identify molecular and neural mechanisms underlying cognitive dysfunction. If successful, the proposed mouse model will reproduce defined biomarker(s) of cognitive dysfunction that can be targeted by known pharmacological molecules to reverse the physiological and cognitive symptoms related to abnormal fear generalization and discrimination. The proposed research is directly relevant to the mission of the NIH, addressing impaired cognitive function caused by maladaptations in prefrontal cortex/amygdala circuits, likely to be associated with neural processes underlying neuropsychiatric disorders such as post-traumatic stress disorder (PTSD).