title: Phenotypic effects of maternal immune activation and early postnatal milieu in mice mutant for the schizophrenia risk gene neuregulin-1.
abstract: Risk of schizophrenia is likely to involve gene × environment (G × E) interactions. Neuregulin 1 (NRG1) is a schizophrenia risk gene, hence any interaction with environmental adversity, such as maternal infection, may provide further insights into the basis of the disease. This study examined the individual and combined effects of prenatal immune activation with polyriboinosinic-polyribocytidilic acid (Poly I:C) and disruption of the schizophrenia risk gene NRG1 on the expression of behavioral phenotypes related to schizophrenia. NRG1 heterozygous (NRG1 HET) mutant breeding pairs were time-mated. Pregnant dams received a single injection (5mg/kg i.p.) of Poly I:C or vehicle on gestation day 9 (GD9). Offspring were then cross-fostered to vehicle-treated or Poly I:C-treated dams. Expression of schizophrenia-related behavioral endophenotypes was assessed at adolescence and in adulthood. Combining NRG1 disruption and prenatal environmental insult (Poly I:C) caused developmental stage-specific deficits in social behavior, spatial working memory and prepulse inhibition (PPI). However, combining Poly I:C and cross-fostering produced a number of behavioral deficits in the open field, social behavior and PPI. This became more complex by combining NRG1 deletion with both Poly I:C exposure and cross-fostering, which had a robust effect on PPI. These findings suggest that concepts of G × E interaction in risk of schizophrenia should be elaborated to multiple interactions that involve individual genes interacting with diverse biological and psychosocial environmental factors over early life, to differentially influence particular domains of psychopathology, sometimes over specific stages of development.
authors: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: C
authors: C
authors: O'Leary
authors: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: L
authors: L
authors: Desbonnet
authors: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: N
authors: N
authors: Clarke
authors: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: E
authors: E
authors: Petit
authors: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: O
authors: O
authors: Tighe
authors: Victor Chang Cardiac Research Institute, University of New South Wales, Darlinghurst, Australia.
authors: D
authors: D
authors: Lai
authors: Victor Chang Cardiac Research Institute, University of New South Wales, Darlinghurst, Australia.
authors: R
authors: R
authors: Harvey
authors: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: J L
authors: JL
authors: Waddington
authors: Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland; School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland. Electronic address: c.otuathaigh@ucc.ie.
authors: C
authors: C
authors: O'Tuathaigh
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D058068:Endophenotypes; D005260:Female; D059647:Gene-Environment Interaction; D008297:Male; D008425:Maternal Behavior; D008569:Memory Disorders / Q000503:physiopathology; D008570:Memory, Short-Term / Q000502:physiology; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000276:immunology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D065808:Prepulse Inhibition / Q000502:physiology; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics; D012919:Social Behavior; D065852:Spatial Memory / Q000502:physiology
chemical_list: D016207:Cytokines; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D011070:Poly I-C
keywords: Poly I:C; behavioral phenotype; cytokines; gene×environment interaction; schizophrenia