title: Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene × environment interaction.
abstract: There is a paucity of animal models by which the contributions of environmental and genetic factors to the pathobiology of psychosis can be investigated. This study examined the individual and combined effects of chronic social stress during adolescence and deletion of the schizophrenia risk gene neuregulin-1 (NRG1) on adult mouse phenotype. Mice were exposed to repeated social defeat stress during adolescence and assessed for exploratory behaviour, working memory, sucrose preference, social behaviour and prepulse inhibition in adulthood. Thereafter, in vitro cytokine responses to mitogen stimulation and corticosterone inhibition were assayed in spleen cells, with measurement of cytokine and brain-derived neurotrophic factor (BDNF) mRNA in frontal cortex, hippocampus and striatum. NRG1 mutants exhibited hyperactivity, decreased anxiety, impaired sensorimotor gating and reduced preference for social novelty. The effects of stress on exploratory/anxiety-related parameters, spatial working memory, sucrose preference and basal cytokine levels were modified by NRG1 deletion. Stress also exerted varied effect on spleen cytokine response to concanavalin A and brain cytokine and BDNF mRNA expression in NRG1 mutants. The experience of psychosocial stress during adolescence may trigger further pathobiological features that contribute to the development of schizophrenia, particularly in those with underlying NRG1 gene abnormalities. This model elaborates the importance of gene × environment interactions in the etiology of schizophrenia.
authors.affiliation: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. lievedesbonnet@rcsi.ie
authors.forename: Lieve
authors.initials: L
authors.lastname: Desbonnet
authors.forename: Colm
authors.initials: C
authors.lastname: O'Tuathaigh
authors.forename: Gerard
authors.initials: G
authors.lastname: Clarke
authors.forename: Claire
authors.initials: C
authors.lastname: O'Leary
authors.forename: Emilie
authors.initials: E
authors.lastname: Petit
authors.forename: Niamh
authors.initials: N
authors.lastname: Clarke
authors.forename: Orna
authors.initials: O
authors.lastname: Tighe
authors.forename: Donna
authors.initials: D
authors.lastname: Lai
authors.forename: Richard
authors.initials: R
authors.lastname: Harvey
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis; D003345:Corticosterone / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004777:Environment; D005106:Exploratory Behavior; D059647:Gene-Environment Interaction; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000235:genetics*; D010641:Phenotype; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology; D012919:Social Behavior; D013315:Stress, Psychological / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D003345:Corticosterone