TARGETED DISRUPTION OF NMDA RECEPTOR-1 GENE ABOLISHES NMDA RESPONSE AND RESULTS IN NEONATAL DEATH

In vitro studies have suggested that the NMDA receptor consists of an essential subunit, NR1, and various modulatory NR2 subunits. To test t his hypothesis directly in vivo, we generated mice carrying a disrupte d NR1 allele. NMDA-inducible increases in intracellular calcium and me mbrane 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 NM DA receptor. A concomitant reduction in levels of NR2B but not NR2A oc curred in NR1(-/-) mice, demonstrating that there is an interdependenc e of subunit expression. NR1(-/-) mice died 8-15 hr after birth, indic ating a vital neonatal function for the NMDA receptor. Although the NM DA receptor has been implicated in several aspects of neurodevelopment , overall neuroanatomy of NR1(-/-) appeared normal. Pathological evide nce suggested that respiratory failure was the ultimate cause of death .