Behavioral deficits and subregion-specific suppression of LTP in mice expressing a population of mutant NMDA receptors throughout the hippocampus.
The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1(N598R) allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs. Surprisingly, these animals revealed specific functional changes in the dentate gyrus (DG) of the hippocampal formation. Early LTP was expressed normally in area CA1 in vivo, but was completely suppressed at perforant path-granule cell synapses in the DG. In addition, there was a pronounced reduction in the amplitude of the evoked population spike in the DG. These specific changes were accompanied by behavioral impairments in spatial recognition, spatial learning, reversal learning, and retention. Our data show that minor changes in GluN1-dependent NMDAR physiology can cause dramatic consequences in synaptic signaling in a subregion-specific fashion despite the nonredundant nature of the GluN1 gene and its global expression.
Laboratory for Molecular Pharmacology, University College London, London WC1E 6BT, United Kingdom. philip.chen@rhul.ac.uk
Philip E
PE
Chen
Michael L
ML
Errington
Matthias
M
Kneussel
Guiquan
G
Chen
Alexander J
AJ
Annala
York H
YH
Rudhard
Georg F
GF
Rast
Christian G
CG
Specht
Cezar M
CM
Tigaret
Mohammed A
MA
Nassar
Richard G M
RG
Morris
Timothy V P
TV
Bliss
Ralf
R
Schoepfer
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000502:physiology*; D007150:Immunohistochemistry; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009473:Neuronal Plasticity / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016194:Receptors, N-Methyl-D-Aspartate