Seizure responses and induction of Fos by the NMDA Agonist (tetrazol-5-yl)glycine in a genetic model of NMDA receptor hypofunction

Abstract

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.Section 3-Neurophysiology, Neuropharmacology and other forms of Intercellular Communication

Increased sensitivity to kainic acid in a genetic model of reduced NMDA receptor function

“…In contrast to the similar or enhanced Fos responses to kainic acid in the NR1 neo/neo mice, induction of Fos in the mutant mice after challenge with sub-seizure doses of a selective NMDA agonist (tertrazol 5yl-gycine) was greatly reduced in cerebral cortical regions, hippocampus, and amygdala (Inada et al, 2007; Duncan et al, 2008). However, we were surprised to find that there was no decreased sensitivity to seizure-producing effects of tetrazol 5yl-glycine in the mutant mice (Duncan et al, 2008).…”

“…However, we were surprised to find that there was no decreased sensitivity to seizure-producing effects of tetrazol 5yl-glycine in the mutant mice (Duncan et al, 2008). Despite the marked reduction in tetrazol 5yl glycine-induced Fos in regions noted above, the mutant and wild type mice showed robust and equivalent induction of Fos in the ventral medial and arcuate nuclei of the hypothalamus, lateral septum, and nucleus of the solitary tract.…”

Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress

“…However, amphetamine-induced Fos was not different in the caudate and accumbens in NR1 neo/neo compared to NR1 +/+ mice (Miyamoto et al, 2004; Ramsey et al, 2008). Fos responses to the direct NMDA agonist tetrazol-5yl glycine were markedly reduced in hippocampus, cingulate cortex, and amygdala in the NR1 hypomorphic mice (Inada et al, 2007; Duncan et al, 2008). Surprisingly, induction of Fos in the NR1 +/+ and NR1 neo/neo mice by the NMDA agonist was similar in a number of subcortical brain regions, including lateral septum, nucleus accumbens, bed nucleus of the stria terminalis, ventromedial hypothalamus, arcuate nucleus of the hypothalamus, and nucleus of the solitary tract (Duncan et al, 2008).…”

“…Fos responses to the direct NMDA agonist tetrazol-5yl glycine were markedly reduced in hippocampus, cingulate cortex, and amygdala in the NR1 hypomorphic mice (Inada et al, 2007; Duncan et al, 2008). Surprisingly, induction of Fos in the NR1 +/+ and NR1 neo/neo mice by the NMDA agonist was similar in a number of subcortical brain regions, including lateral septum, nucleus accumbens, bed nucleus of the stria terminalis, ventromedial hypothalamus, arcuate nucleus of the hypothalamus, and nucleus of the solitary tract (Duncan et al, 2008). Furthermore, there was no difference between the wild type and mutant animals in seizure sensitivity to tetrazol-5yl glycine.…”

“…However, no deficits in Fos induction were observed in these regions following tetrazol-5yl glycine treatment (Duncan et al, 2008). It is therefore possible that some of the activation deficits in these regions in mice tested in the resident-intruder procedure are not directly related to reduced NMDA receptor sensitivity in those regions.…”