Project Summary

Andres Villa Maricq, M.D., Ph.D. (Independent Investigator 2003) of University of Utah, will seek to identify gene products that are required for glutamate receptor (NMDA) function. The treatment of schizophrenia and depression relies heavily on drugs that modify neurotransmission in the central nervous system. Glutamate is the major excitatory neurotransmitter in the brain and exerts its actions by binding to several classes of glutamate-activated receptors. Administration of drugs that block one class of these NMDA receptors causes symptoms in humans that mimic those found in schizophrenics and cause worsening of symptoms when administered to schizophrenia patients. Conversely, drugs that enhance NMDA receptor activity can improve symptoms in schizophrenia patients. Genetic manipulation of NMDA receptor function in mice leads to altered locomotion and stereotypic behaviors reminiscent of the altered behaviors observed in patients with schizophrenia. Moreover, drugs that are used to treat schizophrenia can ameliorate the symptoms observed in these genetically altered mice. These observations all suggest that altered function of NMDA receptors can contribute to the symptoms of schizophrenia. For glutamate to properly activate NMDA receptors, the receptors need to be precisely localized to points of neuron—neuron contact called synapses. Using a genetic approach to identify these gene products, Dr. Maricq will use two strategies to identify genes that contribute to NMDA-dependent signaling. The first strategy will screen for modifiers of a dominantly active NMDA receptor. For these experiments, a hyperactive version of an NMDA receptor will be introduced into transgenic C. elegans nematodes (a worm model). The second strategy will screen for modifiers of NMDA-receptor dependent behaviors. He will clone the genes, determine their site of expression and mode of action, and characterize changes in neurotransmission in mutant animals. This research will provide important information for a molecular-based understanding of schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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