Project Summary

Rebecca J. Ralph, Ph.D. (Young Investigator 2005) of McLean Hospital and Harvard University, plans to study in a rodent model the effect of D-serine levels on behavior in the animal that mimics symptoms of schizophrenia. D-serine, a naturally occurring compound in the brain that increases NMDA receptor activity, improves symptoms in medicated schizophrenic patients. A current theory as to the cause of schizophrenia relates to a decrease in brain NMDA receptor function. Evidence for this hypothesis comes from reports that drugs, such as phencyclidine (i.e., PCP, angel dust), that block NMDA receptors produce some symptoms in normal subjects that are similar to those of schizophrenia patients. All these data suggest that D-serine may play a critical role in the treatment of schizophrenia. Serine racemase contributes to D-serine production in the brain. By altering the presence of serine racemase related genes, researchers have been able to create genetically engineered mice that have no D-serine or abnormally high amounts of D-serine relative to normal mice. These genetically altered mice provide an opportunity to investigate the effects of D-serine in two behavioral models that have been used extensively in preclinical schizophrenia research: prepulse inhibition (an operational model of sensorimotor gating) and locomotor activity. Dr. Ralph hypothesizes that mice that lack D-serine will have decreased NMDA receptor function, deficits in prepulse inhibition similar to those seen in schizophrenia patients and hyperactivity. If this prediction is accurate, she will test whether antipsychotic medications will block these schizophrenic-like behaviors in the mouse model. She also predicts predict that mice with too much D-serine will be protected against PCP-like changes in prepulse inhibition and locomotor activity. Results may provide insights into the underlying mechanisms and treatment of schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia\Molecular

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