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

Abstract

Mice with reduced expression of the NR1 subunit of the NMDA receptor (NR1 hypomorphic mice) display altered behavioral phenotypes that may relate to behavioral characteristics of schizophrenia. Altered phenotypes in the NR1 hypomorphs include marked deficits in species-typical behavioral interactions in tests of social aggression and social affiliation. To gain insight into neuroanatomical circuits disrupted by reduced NMDA receptor function, the present work compared regional brain activation in NR1 hypomorphic mice and their wild type controls after a resident-intruder test. Induction of Fos protein was used as an index of neuronal activation. Wild type mice exhibited robust induction of Fos in select brain regions, including specific nuclei of the hypothalamus and amygdala, lateral septum, and widespread regions of the cerebral cortex. Although the behavioral patterns were different for male and female mice, neuroanatomical patterns of Fos induction were remarkably similar for the two sexes. To determine socially specific components of Fos induction by the residentintruder test, responses were compared for mice assessed in a test of general arousal and stress involving forced swim. Some common brain regions were activated by both tests but regionally specific differences were also found. The NR1 hypomorphic mice tested in the resident-intruder procedure displayed distinctly different behavioral interactions compared to the wild type mice and exhibited a significantly blunted Fos response in almost all brain regions. The mutant mice also exhibited reduced Fos in response to swim stress in specific brain regions. These data suggest that the NR1 hypomorphic mice have functional activation deficits in response to social challenge and swim stress.

Grin1 deletion in CRF neurons sex-dependently enhances fear, sociability, and social stress responsivity

“…This effect was attributed to deletion of Grin1 specifically within CRF neurons of the CeA, suggesting NMDA-dependent regulation of CRF neurons in this region may play an important role in regulating appropriate fear responses. Global Grin1 hypomorphic mice show reduced social engagement accompanied by deficiencies in aggression (Duncan et al, 2009(Duncan et al, , 2004. Decreases in fos activation in the CeA and BNST were also observed in these socially stressed Grin1 hypomorphs (Duncan et al, 2009).…”

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

“…In this respect, differences between phencyclidine (PCP) and MK-801 also became obvious (Baier et al 2009) (Gilmour et al 2009;Seillier and Giuffrida 2009). NR1-hypomorphic mice (Duncan et al 2009), and more specifically a cell-type-specific knockout of NR1 subunits in parvalbumin-positive GABAergic interneurons (Belforte et al 2010), show a phenotype closely reminiscent of schizophrenic pathology.…”

Brain Pathways Mediating the Pro-Aggressive Effect of the Steroid Sulfatase (Sts) Gene

“…Sult2a1et 2 belong to the sulfotransferase family 2A. Sumf1 and 2 sulfatase-modifying factor 1, Gabra1, Gabra2, Gabra3 and Gabrb1 and Gabrb2 GABA A subunits, Grin1 NMDA subunit carring the neurosteroid recognition site, Cyp cytochrome P450 techniques result in a modulation of social behavior and particularly of aggression in mice (Chen et al 1994;Belosertseva and Bespalov 1999;Miyakawa et al 2001;Duncan et al 2009;Sustková-Fiserová et al 2009). The functionality of the NMDA system is generally associated with propensity to display attack behavior but the direction of the association varies with the rearing and testing conditions.…”

“…The direction of the modulation seems independent of the rearing conditions and of the test (resident intruder or neutral cage). Sulfated steroids block the GABA system and stimulate the main excitatory neurotransmitter (N-methyl D-aspartate) (Duncan et al 2009;Sustková-Fiserová et al 2009). High STS concentrations, which are expected to induce low concentrations of sulfated steroids, should increase the incidence of attack behavior, but the experimental findings were the opposite.…”