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Schizophr Bull. 2017 Jan;43(1):214-225. doi: 10.1093/schbul/sbw120. Epub 2016 Sep 9.

Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1.

Author information

1
School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland; c.otuathaigh@ucc.ie.
2
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
3
Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita` degli Studi di Milano, Milan, Italy.
4
Neurogastroenterology Laboratory, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Cork, Ireland.
5
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
6
IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany.
7
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
8
Department of Psychiatry, University College Cork, Cork, Ireland.
9
Victor Chang Cardiac Research Institute, Sydney, Australia.
10
Jiangsu Key Laboratory of Translational Research & Therapy for Neuro-Psychiatric-Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.

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.

KEYWORDS:

endophenotypes; gene × gene interaction; genetic mouse model; psychosis

PMID:
27613806
PMCID:
PMC5216856
DOI:
10.1093/schbul/sbw120
[Indexed for MEDLINE]
Free PMC Article

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