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.
| Butler, Pamela D; Schechter, Isaac; Revheim, Nadine et al. (2010) Has an important test been overlooked? Closure flexibility in schizophrenia. Schizophr Res 118:20-5 |
| Leitman, David I; Laukka, Petri; Juslin, Patrik N et al. (2010) Getting the cue: sensory contributions to auditory emotion recognition impairments in schizophrenia. Schizophr Bull 36:545-56 |
| Leitman, David I; Sehatpour, Pejman; Shpaner, Marina et al. (2009) Mismatch negativity to tonal contours suggests preattentive perception of prosodic content. Brain Imaging Behav 3:284-91 |
| Javitt, Daniel C (2008) Phenomenology, aetiology and treatment of schizophrenia. Novartis Found Symp 289:4-16;discussion 17-22, 87-93 |
| Butler, Pamela D; Tambini, Arielle; Yovel, Galit et al. (2008) What's in a face? Effects of stimulus duration and inversion on face processing in schizophrenia. Schizophr Res 103:283-92 |
| Javitt, Daniel C; Spencer, Kevin M; Thaker, Gunvant K et al. (2008) Neurophysiological biomarkers for drug development in schizophrenia. Nat Rev Drug Discov 7:68-83 |
| Kurylo, Daniel D; Pasternak, Roey; Silipo, Gail et al. (2007) Perceptual organization by proximity and similarity in schizophrenia. Schizophr Res 95:205-14 |
| Javitt, Daniel C; Rabinowicz, Esther; Silipo, Gail et al. (2007) Encoding vs. retention: differential effects of cue manipulation on working memory performance in schizophrenia. Schizophr Res 91:159-68 |
| Butler, Pamela D; Martinez, Antigona; Foxe, John J et al. (2007) Subcortical visual dysfunction in schizophrenia drives secondary cortical impairments. Brain 130:417-30 |
| Linn, Gary S; O'Keeffe, Robert T; Lifshitz, Kenneth et al. (2007) Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine. Psychopharmacology (Berl) 192:27-38 |
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