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

Desbonnet, L., Cox, R., Tighe, O., Lai, D., Harvey, R. P., Waddington, J. L. and O'Tuathaigh, C. M.P. (2017) Altered cytokine profile, pain sensitivity, and stress responsivity in mice with co-disruption of the developmental genes Neuregulin-1 × DISC1. Behavioural Brain Research, 320, pp. 113-118. (doi: 10.1016/j.bbr.2016.11.049) (PMID:27916686)

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, IL1 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 IL1. Epistatic effects were evident for IL6, IL12 and TNF. 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 proinflammatory cytokine levels relative to the effects of each of these genes individually, highlighting the importance of epistatic mechanisms in immune-related pathology.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Desbonnet, Dr Lieve
• Authors: Desbonnet, L., Cox, R., Tighe, O., Lai, D., Harvey, R. P., Waddington, J. L., and O'Tuathaigh, C. M.P.
• Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Behavioural Brain Research
• Publisher: Elsevier
• ISSN: 0166-4328
• ISSN (Online): 0166-4328
• Published Online: 01 December 2016
• Copyright Holders: Copyright © 2017 Elsevier
• First Published: First published inBehavioural Brain Research 320:113-118
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher