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

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.

• Authors: Colm M P O'Tuathaigh, Fabio Fumagalli, Lieve Desbonnet, Francesc Perez-Branguli, Gerard Moloney, Samim Loftus, Claire O'Leary, Emilie Petit, Rachel Cox, Orna Tighe, Gerard Clarke, Donna Lai, Richard P Harvey, John F Cryan, Kevin J Mitchell, Timothy G Dinan, Marco A Riva, John L Waddington
• Journal: Schizophrenia bulletin (Schizophr Bull) Vol. 43 Issue 1 Pg. 214-225 (01 2017) ISSN: 1745-1701 [Electronic] United States
• PMID: 27613806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Amphetamines
• Disc1 protein, mouse
• Nerve Tissue Proteins
• Neuregulin-1
• Nrg1 protein, mouse
• Vasopressins
• Oxytocin

Topics

• 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, metabolism)
• Nesting Behavior
• Neuregulin-1 (genetics, metabolism)
• Oxytocin (metabolism)
• Prepulse Inhibition (genetics)
• Psychomotor Agitation (genetics)
• Psychotic Disorders (genetics, metabolism, physiopathology)
• Schizophrenia (genetics, metabolism, physiopathology)
• Social Behavior
• Vasopressins (metabolism)