Biomarkers of NMDA dysfunction and D-serine effects

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Persistent negative and cognitive symptoms are a primary cause of chronic disability and poor long-term outcome in schizophrenia. Deficits involve sensory-level disturbances, as well as abnormalities of higher level cognition. Phencyclidine (PCP) and other antagonists of N-methyl-D-aspartate (NMDA)-mediated neurotransmission induce symptoms and cognitive deficits that closely resemble those of schizophrenia and incorporate sensory, as well as higher cognitive changes, indicating a potentially critical role of NMDA receptors in the etiopathology of negative symptoms and cognitive dysfunction. NMDA receptors are modulated in vivo by glycine and D-serine, which bind to the glycine modulatory site (GMS) of the NMDA receptor complex. Clinical trials with GMS agonists have yielded highly encouraging clinical data with regard to negative symptoms, although effects on neurocognition remain to be determined. The present project will investigate effects of D-serine on neurocognitive deficits associated with schizophrenia, using both eventrelated potential (ERP) and behavioral measures sensitive to bottom-up effects of early cortical dysfunction. The project consists of two components. First, neurocognitive measures will be added to a recently funded study of D-serine treatment in both chronic and prodromal subjects in order to evaluate the degree to which GMS agonist treatment can reverse or prevent neurocognitive deficits associated with schizophrenia. Second, parallel studies in transgenic mouse models will evaluate the degree to which ERP deficits in schizophrenia can be reproduced by genetic manipulations aimed at the NMDA GMS.