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The Journal of Neuroscience, August 1, 2002, 22(15):6713-6723

Severe Impairment of NMDA Receptor Function in Mice Carrying Targeted Point Mutations in the Glycine Binding Site Results in Drug-Resistant Nonhabituating Hyperactivity

Theresa M. Ballard^{1, *}, Meike Pauly-Evers^{2, *}, Guy A. Higgins¹, Abdel-Mouttalib Ouagazzal¹, Vincent Mutel¹, Edilio Borroni¹, John A. Kemp¹, Horst Bluethmann², and James N. C. Kew¹

¹ Preclinical CNS Research and ² Roche Genetics, F. Hoffmann-La Roche Limited, CH-4070 Basel, Switzerland

NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia, and pharmacological and genetic approaches have been used to model such dysfunction. We previously have described two mouse lines carrying point mutations in the NMDA receptor glycine binding site, Grin1^D481N and Grin1^K483Q, which exhibit 5- and 86-fold reductions in receptor glycine affinity, respectively. Grin1^D481N animals exhibit a relatively mild phenotype compatible with a moderate reduction in NMDA receptor function, whereas Grin1^K483Q animals die shortly after birth. In this study we have characterized compound heterozygote Grin1^D481N/K483Q mice, which are viable and exhibited biphasic NMDA receptor glycine affinities compatible with the presence of each of the two mutated alleles. Grin1^D481N/K483Q mice exhibited a marked NMDA receptor hypofunction revealed by deficits in hippocampal long-term potentiation, which were rescued by the glycine site agonist D-serine, which also facilitated NMDA synaptic currents in mutant, but not in wild-type, mice. Analysis of striatal monoamine levels revealed an apparent dopaminergic and serotonergic hyperfunction. Behaviorally, Grin1^D481N/K483Q mice were insensitive to acute dizocilpine pretreatment and exhibited increased startle response but normal prepulse inhibition. Most strikingly, mutant mice exhibited a sustained, nonhabituating hyperactivity and increased stereotyped behavior that were resistant to suppression by antipsychotics and the benzodiazepine site agonist Zolpidem. They also displayed a disruption of nest building behavior and were unable to perform a cued learning paradigm in the Morris water maze. We speculate that the severity of NMDA receptor hypofunction in these mice may account for their profound behavioral phenotype and insensitivity to antipsychotics.

Key words: NMDA receptor; glycine site; schizophrenia; NMDAR1; Grin1; antipsychotics

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^* T.M.B. and M.P.-E. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22156713-11$05.00/0

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