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Functional Consequences of Reduction in NMDA Receptor Glycine
Affinity in Mice Carrying Targeted Point Mutations in the Glycine
Binding Site
James N. C.
Kew1,
Anja
Koester2,
Jean-Luc
Moreau1,
Francois
Jenck1,
Abdel-Mouttalib
Ouagazzal1,
Vincent
Mutel1,
J. Grayson
Richards1,
Gerhard
Trube1,
Guenther
Fischer1,
Alexandra
Montkowski3,
Wolfgang
Hundt3,
Rainer K.
Reinscheid3,
Meike
Pauly-Evers2,
John A.
Kemp1, and
Horst
Bluethmann2
1 Preclinical CNS Research and 2 Roche
Genetics, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland, and
3 Institute of Cell Biochemistry and Clinical Neurobiology,
University of Hamburg, D-22529 Hamburg, Germany
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
Grin1D481N and
Grin1K483Q mutations,
respectively, whereas receptor glutamate affinity remained unaffected.
Homozygous mutant Grin1D481N
animals are viable and fertile and appear to develop normally. However, homozygous mutant Grin1K483Q
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 Grin1D481N or
Grin1K483Q mice. Interestingly,
in situ hybridization and Western blot analysis revealed
changes in the expression levels of NMDA receptor subunits in
Grin1D481N mice relative to wild
type that may represent a compensatory response to the reduction in
receptor glycine affinity. Grin1D481N
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. Preliminary analysis indicated that the mice exhibit a
decreased natural aversion to an exposed environment. The lethal
phenotype of Grin1K483Q 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, providing further evidence for the role of
NMDA receptor activation in these processes.
Key words:
NMDA receptor; glycine site; NMDAR1; Grin1; LTP; spatial
memory
Copyright © 2000 Society for Neuroscience 0270-6474/00/20114037-13$05.00/0
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