Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death

Neuron. 1994 Aug;13(2):325-38. doi: 10.1016/0896-6273(94)90350-6.


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.

MeSH terms

  • Animals
  • Calcium / physiology
  • Cells, Cultured
  • Cerebellum / physiology
  • Gene Expression
  • Glutamates / pharmacology
  • Hippocampus / physiology
  • Mice
  • Mice, Knockout / anatomy & histology*
  • Mutagenesis, Insertional
  • N-Methylaspartate / physiology*
  • Nervous System / embryology
  • RNA, Messenger / genetics
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synaptic Transmission


  • Glutamates
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Calcium