title: Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity.
abstract: 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.
authors.affiliation: Preclinical CNS Research, F. Hoffmann-La Roche Limited, CH-4070 Basel, Switzerland.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ballard
authors.forename: Meike
authors.initials: M
authors.lastname: Pauly-Evers
authors.forename: Guy A
authors.initials: GA
authors.lastname: Higgins
authors.forename: Abdel-Mouttalib
authors.initials: AM
authors.lastname: Ouagazzal
authors.forename: Vincent
authors.initials: V
authors.lastname: Mutel
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.forename: John A
authors.initials: JA
authors.lastname: Kemp
authors.forename: Horst
authors.initials: H
authors.lastname: Bluethmann
authors.forename: James N C
authors.initials: JN
authors.lastname: Kew
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics; D001679:Biogenic Amines / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018755:GABA Agonists / Q000494:pharmacology; D018390:Gene Targeting; D018698:Glutamic Acid / Q000493:pharmacokinetics; D005998:Glycine / Q000819:agonists / Q000378:metabolism* / Q000493:pharmacokinetics; D006579:Heterozygote; D006624:Hippocampus / Q000503:physiopathology; D006948:Hyperkinesis / Q000235:genetics* / Q000503:physiopathology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D051379:Mice; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D017354:Point Mutation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D012694:Serine / Q000031:analogs & derivatives / Q000494:pharmacology; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D001679:Biogenic Amines; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D012694:Serine; D005998:Glycine