title: Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death.
abstract: In vitro studies have suggested that the NMDA receptor consists of an essential subunit, NR1, and various modulatory NR2 subunits. To test this hypothesis directly in vivo, we generated mice carrying a disrupted NR1 allele. NMDA-inducible increases in intracellular calcium and membrane currents were abolished in neurons from homozygous null mutants (NR1-/-). Thus, NR1 has a unique role, which cannot be substituted by any other subunit, in determining the activity of the endogenous NMDA receptor. A concomitant reduction in levels of NR2B but not NR2A occurred in NR1-/- mice, demonstrating that there is an interdependence of subunit expression. NR1-/- mice died 8-15 hr after birth, indicating a vital neonatal function for the NMDA receptor. Although the NMDA receptor has been implicated in several aspects of neurodevelopment, overall neuroanatomy of NR1-/- mice appeared normal. Pathological evidence suggested that respiratory failure was the ultimate cause of death.
authors.affiliation: Roche Institute of Molecular Biology, Nutley, New Jersey 07110.
authors.forename: D
authors.initials: D
authors.lastname: Forrest
authors.forename: M
authors.initials: M
authors.lastname: Yuzaki
authors.forename: H D
authors.initials: HD
authors.lastname: Soares
authors.forename: L
authors.initials: L
authors.lastname: Ng
authors.forename: D C
authors.initials: DC
authors.lastname: Luk
authors.forename: M
authors.initials: M
authors.lastname: Sheng
authors.forename: C L
authors.initials: CL
authors.lastname: Stewart
authors.forename: J I
authors.initials: JI
authors.lastname: Morgan
authors.forename: J A
authors.initials: JA
authors.lastname: Connor
authors.forename: T
authors.initials: T
authors.lastname: Curran
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000502:physiology; D015870:Gene Expression; D005971:Glutamates / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout / Q000033:anatomy & histology*; D016254:Mutagenesis, Insertional; D016202:N-Methylaspartate / Q000502:physiology*; D009420:Nervous System / Q000196:embryology; D012333:RNA, Messenger / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D005971:Glutamates; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D002118:Calcium