Partial genetic deletion of neuregulin 1 modulates the effects of stress on sensorimotor gating, dendritic morphology, and HPA axis activity in adolescent mice

Abstract

Stress has been linked to the pathogenesis of schizophrenia. Genetic variation in neuregulin 1 (NRG1) increases the risk of developing schizophrenia and may help predict which high-risk individuals will transition to psychosis. NRG1 also modulates sensorimotor gating, a schizophrenia endophenotype. We used an animal model to demonstrate that partial genetic deletion of Nrg1 interacts with stress to promote neurobehavioral deficits of relevance to schizophrenia. Nrg1 heterozygous (HET) mice displayed greater acute stress-induced anxiety-related behavior than wild-type (WT) mice. Repeated stress in adolescence disrupted the normal development of higher prepulse inhibition of startle selectively in Nrg1 HET mice but not in WT mice. Further, repeated stress increased dendritic spine density in pyramidal neurons of the medial prefrontal cortex (mPFC) selectively in Nrg1 HET mice. Partial genetic deletion of Nrg1 also modulated the adaptive response of the hypothalamic-pituitary-adrenal axis to repeated stress, with Nrg1 HET displaying a reduced repeated stress-induced level of plasma corticosterone than WT mice. Our results demonstrate that Nrg1 confers vulnerability to repeated stress-induced sensorimotor gating deficits, dendritic spine growth in the mPFC, and an abberant endocrine response in adolescence.

Keywords: PPI; adolescence; dendritic morphology; neuregulin 1; schizophrenia; stress.

Fig. 1.

Examination of the acute and repeated effects of restraint stress on anxiety-related behaviors in adolescent WT and Nrg1 HET mice. (A) Overview of the experimental design. (B) Time in the open arms, and (C) entries in the open arms in the elevated plus maze. (D) Time in the hide box and (E) entries into hide box in the light-dark test. Acute restraint stress significantly increased time in the hide box of Nrg1 HET mice compared with nonstressed Nrg1 HET mice *P < .05. C represents a significant main effect of stress condition in the two factor ANOVA. Data are presented as means ± SEM. WT, wild-type mice; Nrg1 HET, neuregulin 1 heterozygous mice; NS, nonstressed homecage controls; S, mice subjected to restraint stress.

Fig. 2.

Partial genetic deletion of Nrg1 conferred vulnerability to repeated stress-induced prepulse inhibition (PPI) deficits and a blunted HPA axis response to stress in adolescence. (A) %PPI following acute stress, and (B) repeated stress. Repeated restraint stress significantly reduced %PPI in Nrg1 HET mice compared with nonstressed Nrg1 HET mice at 74, 82, and 86 dB prepulse intensities **Ps < .01. (C) Startle response to a 120 dB stimulus. Acute stress significantly reduced the startle response in Nrg1 HET mice compared with nonstressed Nrg1 HET mice *P < .05. (D) Plasma corticosterone concentrations sampled immediately after restraint stress and following recovery from stress when sampled 90 minutes after the restraint stress episode. Acute and repeated stress significantly increased corticosterone compared with respective nonstressed mice in both WT and Nrg1 HET mice ***Ps < .001, ****P < .0001. Following repeated stress, stress-induced plasma corticosterone concentrations were significantly lower in Nrg1 HET mice than WT mice **P < .01. Data are represented as means ± SEM. a.u., arbitrary units; WT, wild-type mice; Nrg1 HET, neuregulin 1 heterozygous mice; NS, nonstressed homecage controls; S, mice subjected to restraint stress; R, mice after 90-minute recovery from acute stress.

Fig. 3.

Partial genetic deletion of Nrg1 promoted a repeated stress-induced increase in apical dendritic spine density and a decrease in dendritic lengths and complexity in layers II/III of the medial prefrontal cortex (mPFC). (A) Dendritic spine density per µm of apical dendrites with increasing dendritic branch order. (B) Dendritic spine density on fourth order dendrites. (C) Cumulative apical dendritic lengths and (D) no. of intersections as determined by Sholl analysis. Repeatedly stressed Nrg1 HET mice exhibited significantly increased dendritic spine density and decreased dendritic lengths and dendritic complexity, in the mPFC compared with nonstressed Nrg1 HET mice or stressed WT mice, *Ps < .05. (E) Representative photomicrographs of Golgi-stained dendritic spines on fourth order apical dendrites in the mPFC, scale bar = 5 µm. (F) Representative tracings of Golgi-stained mPFC apical dendrites in nonstressed vs stressed Nrg1 HET mice, scale bar = 50 µm. WT, wild-type mice; Nrg1 HET, neuregulin 1 heterozygous mice; NS, nonstressed homecage controls; S, mice subjected to restraint stress.

Fig. 4.

Partial genetic deletion of Nrg1 decreased apical dendritic lengths and complexity in pyramidal neurons of the CA1 region of the hippocampus. (A) Dendritic spine density per µm of apical dendrites with increasing dendritic branch order. (B) Cumulative apical dendritic lengths and (C) no. of intersections as determined by Sholl analysis. Nrg1 HET mice exhibited shorter apical dendritic lengths and less dendritic complexity than WT mice in the CA1 region, *P < .05 represents main effect of genotype. (D) Representative tracings of Golgi-stained apical dendrites of pyramidal neurons in the CA1 region of the hippocampus, scale bar = 50 µm. WT, wild-type mice; Nrg1 HET, neuregulin 1 heterozygous mice; NS, nonstressed homecage controls; S, mice subjected to restraint stress.