Roles of NMDA receptors in schizophrenia pathological process

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DESCRIPTION (provided by applicant): Schizophrenia is probably the most distressing and disabling mental disorder. It affects almost 1% of the human population. Although the pathological processes of this disease is still not clear, remarkable progresses have been made in the past decades to solve this mystery. According to the postmortem studies of the brains of schizophrenia patients, it is now clear that certain inhibitory neurons in the forebrain are selectively damaged. In addition, a group of dissociative anesthetics, such as phencyclidine (PCP, Sernyl, also called 'angel dust') and its related compounds MK-801 and ketamine, can produce a wide range of schizophrenia-like symptoms such as estrangement, thought disorder, hallucination, and psychosis in both surgical patients and health volunteers. These drugs could also cause similar damage of inhibitory interneurons in the forebrain of animal models. Since these drugs are also NMDA receptor antagonists, a hypofunction hypothesis of NMDA receptors and inhibitory interneuron has thus been proposed for the schizophrenia pathological process. This intriguing hypothesis has attracted a great deal of attention, but the direct evidence in support of this hypothesis is still lacking. In this proposal, we hypothesize that the receptor properties of a subpopulation of interneurons in the prefrontal cortex are uniquely organized and these properties make them highly vulnerable to environmental factors that cause schizophrenia. The experiments listed in this proposal are designed to provide a comprehensive assessment of the receptor properties on the inhibitory circuitry which are evidenced as one of the most vulnerable parts of the brain in the schizophrenia pathological process. The experiments will be conducted in both normal and MK-801-treated animal models.