Altered cytokine profile, pain sensitivity, and stress responsivity in mice with co-disruption of the developmental genes Neuregulin-1×DISC1

Abstract

The complex genetic origins of many human disorders suggest that epistatic (gene×gene) interactions may contribute to a significant proportion of their heritability estimates and phenotypic heterogeneity. Simultaneous disruption of the developmental genes and schizophrenia risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) in mice has been shown to produce disease-relevant and domain-specific phenotypic profiles different from that observed following disruption of either gene alone. In the current study, anxiety and stress responsivity phenotypes in male and female mutant mice with simultaneous disruption of DISC1 and NRG1 were examined. NRG1×DISC1 mutant mice were generated and adult mice from each genotype were assessed for pain sensitivity (hot plate and tail flick tests), anxiety (light-dark box), and stress-induced hypothermia. Serum samples were assayed to measure circulating levels of pro-inflammatory cytokines. Mice with the NRG1 mutation, irrespective of DISC1 mutation, spent significantly more time in the light chamber, displayed increased core body temperature following acute stress, and decreased pain sensitivity. Basal serum levels of cytokines IL8, IL1β and IL10 were decreased in NRG1 mutants. Mutation of DISC1, in the absence of epistatic interaction with NRG1, was associated with increased serum levels of IL1β. Epistatic effects were evident for IL6, IL12 and TNFα. NRG1 mutation alters stress and pain responsivity, anxiety, and is associated with changes in basal cytokine levels. Epistasis resulting from synergistic NRG1 and DISC1 gene mutations altered pro-inflammatory cytokine levels relative to the effects of each of these genes individually, highlighting the importance of epistatic mechanisms in immune-related pathology.

Neuregulin‐1‐ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide‐induced cystitis

“…In addition, multiple studies have indicated that neuroinflammation, whose importance on neuropathic pain has been shown previously, can yield important insights into the function of Nrg1‐ErbB signaling. For instance, a recent study showed that mice with Nrg1 mutation display decreased pain sensitivity accompanied by decreased basal proinflammatory cytokine levels . In addition, in vivo and in vitro experiments also showed that microglia can be activated when Nrg1 combines with the ErbB2 receptor on the microglial membrane and that the activated microglia can release IL‐1β .…”

“…For instance, a recent study showed that mice with Nrg1 mutation display decreased pain sensitivity accompanied by decreased basal proinflammatory cytokine levels. 22 In addition, in vivo and in vitro experiments also showed that microglia can be activated when Nrg1 combines with the ErbB2 receptor on the microglial membrane and that the activated microglia can release IL-1β. 6 The trigger function of Nrg1 in microglia activation has also been validated in several other studies.…”

Neuregulin 1 Deficiency Modulates Adolescent Stress-Induced Dendritic Spine Loss in a Brain Region-Specific Manner and Increases Complement 4 Expression in the Hippocampus

“…Activation of the complement system triggers inflammation, whereas Nrg1 is anti-inflammatory, implying a counter regulatory relationship between Nrg1 and C4 signaling. 44,57 Altered cytokine profiles in the plasma, spleen, and brain have been demonstrated in Nrg1 HET mice, 46,58 which may then impact upon C4 expression. 59,60 It is noteworthy, that in humans a loss-of-function mis-sense mutation in NRG1 increased plasma levels of numerous autoimmune and inflammatory markers.…”

The effects of preventative cannabidiol in a male neuregulin 1 mouse model of schizophrenia

“…Neuregulin 1 ( NRG1 ) is a well-established genetic risk factor for schizophrenia ( Mostaid et al, 2016 ), and a mutation in the transmembrane domain region of NRG1 is found in patients with schizophrenia ( Walss-Bass et al, 2006 ). A multitude of previous studies, including from our team, have established face, construct, and predictive validity for Nrg1 transmembrane domain heterozygous ( Nrg1 TM HET) mice (review: Karl, 2013 ), which exhibit age-dependent and sex-specific differences in locomotion, sensorimotor gating and social behaviors ( Karl et al, 2007 ; van den Buuse et al, 2009 ; Desbonnet et al, 2017 ) changes to glutamatergic and GABAergic signaling and inflammatory tone ( Desbonnet et al, 2012 ; Long et al, 2012 ; Newell et al, 2013 ; Chohan et al, 2014 ) as well as altered sensitivity to THC ( Boucher et al, 2007 ; Long et al, 2013 ), reflecting findings in clinical cohorts ( Saha et al, 2005 ; Han et al, 2012 ). Specifically, Nrg1 TM HET males exhibit hyperlocomotion in the open field ( Karl et al, 2007 ), deficits in social interaction (SI) ( O’Tuathaigh et al, 2008 ), and deficits in prepulse inhibition (PPI) ( Stefansson et al, 2002 ).…”