title: Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R).
abstract: NMDA receptors in mice were mutated by gene targeting to substitute asparagine (N) in position 598 of the NR1 subunit to glutamine (Q) or arginine (R). Animals expressing exclusively the mutated NR1 alleles, NR1(Q/Q) and NR1(-/R) mice, developed a perinatally lethal phenotype mainly characterized by respiratory failure. The dysfunctions were partially rescued in heterozygous mice by the presence of pure wild-type receptors. Thus, NR1(+/Q) mice exhibited reduced life expectancy, with females being impaired in nurturing; NR1(+/R) mice displayed signs of underdevelopment such as growth retardation and impaired righting reflex, and died before weaning. We analyzed the key properties of NMDA receptors, high Ca(2+) permeability, and voltage-dependent Mg(2+) block, in the mutant mice. Comparison of the complex physiological and phenotypical changes observed in the different mutants indicates that properties controlled by NR1 subunit residue N598 are important for autonomic brain functions at birth and during postnatal development. We conclude that disturbed NMDA receptor signaling mediates a variety of neurological phenotypes.
authors.affiliation: Max-Planck-Institute for Medical Research, Departments of Molecular Neuroscience and Cell Physiology, Jahnstrabetae 29, D-69120 Heidelberg, Germany.
authors.forename: F N
authors.initials: FN
authors.lastname: Single
authors.forename: A
authors.initials: A
authors.lastname: Rozov
authors.forename: N
authors.initials: N
authors.lastname: Burnashev
authors.forename: F
authors.initials: F
authors.lastname: Zimmermann
authors.forename: D F
authors.initials: DF
authors.lastname: Hanley
authors.forename: D
authors.initials: D
authors.lastname: Forrest
authors.forename: T
authors.initials: T
authors.lastname: Curran
authors.forename: V
authors.initials: V
authors.lastname: Jensen
authors.forename: O
authors.initials: O
authors.lastname: Hvalby
authors.forename: R
authors.initials: R
authors.lastname: Sprengel
authors.forename: P H
authors.initials: PH
authors.lastname: Seeburg
mesh_terms: D000483:Alleles; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006720:Homozygote; D017774:Long-Term Potentiation; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D019579:Neocortex / Q000254:growth & development; D010641:Phenotype; D017354:Point Mutation; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000502:physiology*; D012131:Respiratory Insufficiency / Q000235:genetics
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D008274:Magnesium; D002118:Calcium