RRC ID 46361
Author O'Tuathaigh CM, Fumagalli F, Desbonnet L, Perez-Branguli F, Moloney G, Loftus S, O'Leary C, Petit E, Cox R, Tighe O, Clarke G, Lai D, Harvey RP, Cryan JF, Mitchell KJ, Dinan TG, Riva MA, Waddington JL.
Title Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1.
Journal Schizophr Bull
Abstract Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1.
Volume 43(1)
Pages 214-225
Published 2017-1-1
DOI 10.1093/schbul/sbw120
PII sbw120
PMID 27613806
PMC PMC5216856
MeSH Amphetamines / pharmacology Animals Behavior, Animal* Brain / metabolism* Disease Models, Animal Endophenotypes* Epistasis, Genetic* Female Grooming Male Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism* Nesting Behavior Neuregulin-1 / genetics Neuregulin-1 / metabolism* Oxytocin / metabolism Prepulse Inhibition / genetics Psychomotor Agitation / genetics Psychotic Disorders* / genetics Psychotic Disorders* / metabolism Psychotic Disorders* / physiopathology Schizophrenia* / genetics Schizophrenia* / metabolism Schizophrenia* / physiopathology Social Behavior Vasopressins / metabolism
IF 7.958
Times Cited 7
Mice RBRC02324 RBRC02325