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.

Seeing through the smoke: Human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

“…The atypical effect of THC on Nrg1 HET mice appeared to be dependent on stress and correlated with increased activation of stress circuitry in the brain, with pronounced effects in the lateral septum (Boucher et al, 2007b). Interestingly, more recent studies reported that stress decreased expression of Nrg1 in the brain (Brydges et al, 2014; Makinodan et al, 2012), and partial genetic deletion of Nrg1 altered behavioural and neurobiological responses to stress (Chohan et al, 2014a; Chohan et al, 2014b; Desbonnet et al, 2012; Taylor et al, 2011). …”

Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex

“…Partial genetic deletion of Nrg1 conferred vulnerability to the effects of adolescent social defeat stress on spatial working memory function and modulation of inflammatory cytokines in the prefrontal cortex and hippocampus (Desbonnet et al, 2012 ). We have also recently shown that partial genetic deletion of Nrg1 altered neurobehavioral responses to repeated adolescent restraint stress (Chohan et al, 2014 ). Repeated adolescent stress selectively impaired the development of normal sensorimotor gating in Nrg1 heterozygous ( Nrg1 HET) mice which correlated with a dysregulation in stress-induced corticosterone release.…”

“…Male mice were subjected to 30 min/day of restraint stress for 14 days from PND 36 to PND 49 as described in our previous study (Chohan et al, 2014 ). Restraint stress was chosen as it is a well-characterized physical stressor in rodents that activates the HPA axis and increases anxiety-related behavior (Eiland and McEwen, 2010 ; Sutherland et al, 2010 ; Sutherland and Conti, 2011 ; Chesworth et al, 2012 ).…”

Animal models of gene–environment interaction in schizophrenia: A dimensional perspective

“…Acute and repeated stress resulted in increased levels of corticosterone levels, however the response was significantly less in the mutants after repeated stress. Interestingly stress decreased apical dendritic length and complexity in the medial prefrontal cortex and hippocampus of the mutants (Chohan et al, 2014a). NMDA receptor binding of MK-801 was increased but the response was blunted in the ventrolateral septum, more pronounced in the dentate gyrus, and binding was decreased in the inferior-lateral region of the mPFC of the mutants (Chohan et al, 2014b).…”