Knockdown and overexpression of NR1 modulates NMDA receptor function.
The N-methyl-d-aspartate receptor (NMDAR) is critically involved in learning and memory, neuronal survival, as well as neuroexcitotoxicity and seizures. We hypothesize that even mild reductions in the numbers of hippocampal NMDARs could impair learning and memory, whereas increasing receptor activity would facilitate learning but reduce seizure threshold. We developed novel gene transfer strategies assisted by an adeno-associated viral vector 1/2 to bi-directionally modulate expression levels of the NR1 protein in rat hippocampus. Functional consequences of the altered NR1 expression were examined in the acute seizure model, and on normal processes of fear memory and neurogenesis. We found that knocking down NR1 protected against seizures at the expense of impaired learning, as predicted. Paradoxically, NR1 overexpression not only increased fear memory and neurogenesis, but also delayed onset of more severe seizures. In conclusion, the observed consequences of NR1 knockdown and overexpression underscore NMDAR requirement for neuronal plasticity, and are in agreement with its dichotomous functions.
Kalev-Zylinska
Maggie L
ML
Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.
Symes
Wymond
W
Young
Deborah
D
During
Matthew J
MJ
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005239:Fear; D005434:Flow Cytometry / Q000379:methods; D015870:Gene Expression / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D042282:Microdissection / Q000379:methods; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D014162:Transfection / Q000379:methods
D018690:Excitatory Amino Acid Agonists; D008164:Luminescent Proteins; C409466:NR1 NMDA receptor; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine; D007608:Kainic Acid