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

Abstract

Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1) and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs) which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET) and wild-type (WT) mice using [3H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV) and the dentate gyrus (DG) of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL) subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However, in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex.

Adolescent social defeat alters N-methyl-d-aspartic acid receptor expression and impairs fear learning in adulthood

“…Specifically, adolescent social defeat resulted in decreased levels of NMDA receptors in both the central nucleus of the amygdala (CeA) and the infralimbic region of the mPFC, while increased NMDA receptor expression was noted in the CA3 region of the hippocampus. Several other studies have looked at NMDA receptor expression in response to stress, albeit utilizing different quantification methods, developmental time points, and stress procedures [10, 11, 39–45]. While the majority of these studies looked at expression of specific NMDA receptor subunits, one study measuring 3H-MK-801 binding immediately following repeated immobilization stress in adolescent mice found an increase in NMDA expression in the lateral septum and dentate gyrus, but no other regions [10].…”

“…Several other studies have looked at NMDA receptor expression in response to stress, albeit utilizing different quantification methods, developmental time points, and stress procedures [10, 11, 39–45]. While the majority of these studies looked at expression of specific NMDA receptor subunits, one study measuring 3H-MK-801 binding immediately following repeated immobilization stress in adolescent mice found an increase in NMDA expression in the lateral septum and dentate gyrus, but no other regions [10]. Although unique methodologies might partially account for the differences in binding pattern from the present study, the long term effects of a stressor such as social defeat are likely different from changes measured immediately following a physical stressor like immobilization.…”

“…Furthermore, social isolation stress in adolescence causes synaptic loss in the adult prefrontal cortex, which can be reversed by treatment with the NMDA receptor antagonist MK-801 [9]. While changes to NMDA receptor expression, as measured by 3H-MK-801 receptor binding to NMDA receptors, have been found following physical stressors in both adults and adolescents [10, 11], the effects of social stress experienced in adolescence on 3H-MK-801 binding have yet to be evaluated.…”

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

“…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). …”

Schizophrenia: A Consequence of Gene-Environment Interactions?

“…Karl's review overviews a raft of evidence supporting Nrg1 as a key player in the vulnerability of mice to environmental (risk) factors such as stress, cannabis abuse and housing conditions (Karl, 2013). Following on from recent published work (Chohan et al, 2014a), Chohan et al describes research in which partial genetic deletion of Nrg1 modulates the effects of adolescent stress on N-methyl-d-aspartate receptors (NMDAR), with the Nrg1-stress interaction tending to decrease NMDAR binding in the medial prefrontal cortex (Chohan et al, 2014b). This is significant as NMDAR is decreased in brains of schizophrenia patients and implicated in the pathophysiology of the disorder.…”