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Titolo:
Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site
Autore:
Kew, JNC; Koester, A; Moreau, JL; Jenck, F; Ouagazzal, AM; Mutel, V; Richards, JG; Trube, G; Fischer, G; Montkowski, A; Hundt, W; Reinscheid, RK; Pauly-Evers, M; Kemp, JA; Bluethmann, H;
Indirizzi:
F Hoffmann La Roche & Co Ltd, Div Pharma, Preclin CNS Res, CH-4070 Basel, Switzerland F Hoffmann La Roche & Co Ltd Basel Switzerland CH-4070 asel, Switzerland F Hoffmann La Roche & Co Ltd, Roche Genet, CH-4070 Basel, Switzerland F Hoffmann La Roche & Co Ltd Basel Switzerland CH-4070 asel, Switzerland Univ Hamburg, Inst Cell Biochem & Clin Neurobiol, D-22529 Hamburg, GermanyUniv Hamburg Hamburg Germany D-22529 Neurobiol, D-22529 Hamburg, Germany
Titolo Testata:
JOURNAL OF NEUROSCIENCE
fascicolo: 11, volume: 20, anno: 2000,
pagine: 4037 - 4049
SICI:
0270-6474(20000601)20:11<4037:FCORIN>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
D-ASPARTATE RECEPTOR; LONG-TERM POTENTIATION; PREPULSE INHIBITION; DEVELOPMENTAL-CHANGES; XENOPUS OOCYTES; NR2B SUBUNIT; AMINO-ACIDS; RAT-BRAIN; IN-VITRO; ANTAGONIST;
Keywords:
NMDA receptor; glycine site; NMDAR1; Grin1; LTP; spatial memory;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Kew, JNC F Hoffmann La Roche & Co Ltd, Div Pharma, Preclin CNS Res, Bldg 70-343, CH-4070 Basel, Switzerland F Hoffmann La Roche & Co Ltd Bldg 70-343 Basel Switzerland CH-4070
Citazione:
J.N.C. Kew et al., "Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site", J NEUROSC, 20(11), 2000, pp. 4037-4049

Abstract

We have used site-directed mutagenesis in conjunction with homologous recombination to generate two mouse lines carrying point mutations in the glycine binding site of the NMDAR1 subunit (Grin1). Glycine concentration-response curves from acutely dissociated hippocampal neurons revealed a 5- and 86-fold reduction in receptor glycine affinity in mice carrying Grin1(D481N) and Grin1(K483Q) mutations, respectively, whereas receptor glutamate affinity remained unaffected. Homozygous mutant Grin1(D481N) animals are viable and fertile and appear to develop normally. However, homozygous mutant Grin1(K483Q) animals are significantly lighter at birth, do not feed, and die within a few days. No gross abnormalities in CNS anatomy were detected in either Grin1(D481N) or Grin1(K483Q) mice. Interestingly, in situ hybridizationand Western blot analysis revealed changes in the expression levels of NMDA receptor subunits in Grin1(D481N) mice relative to wild type that may represent a compensatory response to the reduction in receptor glycine affinity. Grin1(D481N) mice exhibited deficits in hippocampal theta burst-induced long-term potentiation (LTP) and spatial learning and also a reduction in sensitivity to NMDA-induced seizures relative to wild-type controls, consistent with a reduced activation of NMDA receptors. Mutant mice exhibited normal prepulse inhibition but showed increased startle reactivity. Preliminaryanalysis indicated that the mice exhibit a decreased natural aversion to an exposed environment. The lethal phenotype of Grin1(K483Q) animals confirms the critical role of NMDA receptor activation in neonatal survival. A milder reduction in receptor glycine affinity results in an impairment of LTP and spatial learning and alterations in anxiety-related behavior, providingfurther evidence for the role of NMDA receptor activation in these processes.

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Documento generato il 29/02/20 alle ore 15:01:26