Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R)

NMDA receptors in mice were mutated by gene targeting to substitute asparag ine (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 heterozygo us mice by the presence of pure wild-type receptors. Thus, NR1(+/Q) mice ex hibited reduced life expectancy, with females being impaired in nurturing; NR1(+/R) mice displayed signs of underdevelopment such as growth retardatio n and impaired righting reflex, and died before weaning. We analyzed the ke y properties of NMDA receptors, high Ca2+ permeability, and voltage-depende nt Mg2+ block, in the mutant mice. Comparison of the complex physiological and phenotypical changes observed in the different mutants indicates that p roperties controlled by NR1 subunit residue N598 are important for autonomi c brain functions at birth and during postnatal development. We conclude th at disturbed NMDA receptor signaling mediates a variety of neurological phe notypes.