Seizure responses and induction of Fos by the NMDA agonist (tetrazol-5-yl)glycine in a genetic model of NMDA receptor hypofunction.
Effects of the direct NMDA agonist (tetrazol-5-yl)glycine (TZG) were examined in a genetic mouse model of reduced NMDA receptor function. In this model, expression of the NR1 subunit is reduced but not eliminated and the mice are therefore designated as NR1 hypomorphic. Previous work suggested that the reduced NR1 subunit expression produced a functional subsensitivity as judged by a blunted Fos induction response to a sub-seizure dose of TZG. In the present study seizure threshold doses of TZG were tested in the wild type and mutant mice. Surprisingly, there was no difference in the seizure sensitivity between the wild type mice and mice presumed to express very low levels of the NR1 subunit. An extensive neuroanatomical analysis of Fos induction was conducted after the threshold seizure doses of TZG. The results demonstrate that some brain regions of the NR1 -/- mice exhibit much lower Fos induction in comparison to the NR1 +/+ mice. These regions include hippocampus, amygdala, and cerebral cortical regions. However, in other regions, similar induction of Fos was observed in both genotypes in response to the NMDA agonist. Regions showing similar Fos induction in the NR1 +/+ and NR1 -/- mice include the lateral septum, nucleus of the solitary tract, and medial hypothalamic regions. The results suggest that the NMDA receptor hypofunction in the NR1 -/- mice is not global but regionally specific and that subcortical structures are responsible for the seizure-inducing effects of TZG.
Duncan
Gary E
GE
Department of Psychiatry, 410 Taylor Hall, CB 7090, University of North Carolina, Chapel Hill, NC 27599, USA. gduncan@med.unc.edu
Inada
Ken
K
Farrington
Joseph S
JS
Koller
Beverly H
BH
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000235:genetics*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; C409466:NR1 NMDA receptor; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; C073649:(tetrazol-5-yl)glycine; D018698:Glutamic Acid; D005998:Glycine