Neurophysiological NMDA dysfunction in schizophrenia

New York University School Of Medicine, New York NY

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Abstract

DESCRIPTION: (provided by applicant) This is a first time competing continuation application for a K02 Independent Scientist Award. Phencyclidine (PCP) induces a psychotic state that closely resembles schizophrenia by blocking neurotransmission at the N-methyl-D-asparate (NMDA)-type glutamate receptor. The ability of NMDA antagonists to induce schizophrenia-like symptoms indicates that endogenous NMDA receptor dysfunction or dysregulation may contribute substantially to the pathophysiology of schizophrenia. This K02 award will enable the applicant to pursue investigations directed to the continued development of the PCPINMDA model of schizophrenia. Specific projects will include (1) characterization of neurophysiological and neurocognitive dysfunction in schizophrenia relative to the predictions of the PCP/NMDA model, (2) investigation of mechanisms underlying neurophysiological and neurocognitive dysfunction in schizophrenia using multichannel intracortical recordings in animals, (3) neurochemical investigation of NMDA/dopamine interactions, (4) determination of the effects of NMDA augmenting agents on negative symptoms and cognitive functioning in schizophrenia, and (5) development of novel, clinically relevant NMDA augmentation strategies. Neurophysiological studies will focus on impaired generation of mismatch negativity (MMN), auditory N 1 and other sensory/cognitive components in schizophrenia. Neurochemical studies will evaluate the ability of glycine or other NMDA agonists (e.g., D-cycloserine, D-serine) or of glycine transport inhibitors to reverse PCP-induced neurochemical abnormalities. Treatment studies will focus on the use of glycine, D-cycloserine and related agents in the management of persistent negative and cognitive symptoms of schizophrenia. The research will build upon studies currently supported by NIH research and career development awards to the candidate, and will permit the candidate to continue to devote >75 percent effort to research.