title: 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.
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; School of Life Sciences, West Medical Building, University of Glasgow, Glasgow, UK.
authors.forename: Lieve
authors.initials: L
authors.lastname: Desbonnet
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cox
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Orna
authors.initials: O
authors.lastname: Tighe
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, Australia.
authors.forename: Donna
authors.initials: D
authors.lastname: Lai
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, Australia.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland. Electronic address: c.otuathaigh@ucc.ie.
authors.forename: Colm M P
authors.initials: CM
authors.lastname: O'Tuathaigh
mesh_terms: D000221:Adaptation, Ocular; D000704:Analysis of Variance; D000818:Animals; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D005334:Fever / Q000209:etiology; D006930:Hyperalgesia / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D012737:Sex Factors; D013315:Stress, Psychological / Q000150:complications
chemical_list: D016207:Cytokines; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse
keywords: Anxiety; Cytokines; Disrupted-in-schizophrenia-1; Neuregulin-1; Stress responsivity