Genetic, post-mortem and psychopharmacologic findings support the hypothesis that hypofunction of NMDA? receptors may contribute symptomatic manifestations of schizophrenia. One potential mechanism is through? the glycine modulatory site on the NMDA receptor, which must be occupied by glycine/D-serine, for the? NMDA receptor to function. The association of the risk for schizophrenia with the gene encoding G72, a? protein that activates D-amino acid oxidase that degrades D-serine, suggests low D-serine, which has been? reported in schizophrenia, could be one cause of NMDA receptor hypofunction. To understand better the? role of D-serine in hippocampal physiology and behavior, we will pursue two strategies. First, we will use our? mice with floxed serine racemase gene to suppress its expression at 4 weeks pot-partum and characterize? the neurophysiologic and behavioral consequences. Secondly, we will characterize the effects of transfected? G72 on D-amino acid oxidase activity and D-serine levels in vitro, in tissue culture and in vivo using? transgenic techniques. Finally, N-acetyl aspartyl glutamate (NAAG) is catabolized by glutamate? Carboxypeptidase II (GCPII). NAAG is a selective agonist at mGluR3 (GRM3), whose gene has been? associated with risk for schizophrenia; and GCPII expression is reduced in schizophrenia. We will use our? mice with floxed GCPII to suppress its expression at 4 weeks post-partum and characterize the? neurophysiologic and behavioral consequences. We believe that these experiments should provide? informative mutant mice that should share homologies in behavior and synaptic chemistry to schizophrenia? and will permit correlating cognitive deficits defined by the same tasks in patients and mice to hippocampal? electrophysiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH060450-08
Application #
7426295
Study Section
Special Emphasis Panel (ZMH1)
Project Start
2007-06-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
8
Fiscal Year
2007
Total Cost
$314,782
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
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