Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1.
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.
School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland; c.otuathaigh@ucc.ie.|Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Colm M P
CM
O'Tuathaigh
Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita` degli Studi di Milano, Milan, Italy.
Fabio
F
Fumagalli
Neurogastroenterology Laboratory, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Cork, Ireland.
Lieve
L
Desbonnet
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.|IZKF Junior Research Group and BMBF Research Group Neuroscience, IZKF, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany.
Francesc
F
Perez-Branguli
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Gerard
G
Moloney
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Samim
S
Loftus
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Claire
C
O'Leary
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Emilie
E
Petit
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Rachel
R
Cox
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Orna
O
Tighe
Neurogastroenterology Laboratory, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Cork, Ireland.|Department of Psychiatry, University College Cork, Cork, Ireland.
Gerard
G
Clarke
Victor Chang Cardiac Research Institute, Sydney, Australia.
Donna
D
Lai
Victor Chang Cardiac Research Institute, Sydney, Australia.
Richard P
RP
Harvey
Neurogastroenterology Laboratory, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
John F
JF
Cryan
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
Kevin J
KJ
Mitchell
Neurogastroenterology Laboratory, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Cork, Ireland.|Department of Psychiatry, University College Cork, Cork, Ireland.
Timothy G
TG
Dinan
Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita` degli Studi di Milano, Milan, Italy.
Marco A
MA
Riva
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.|Jiangsu Key Laboratory of Translational Research & Therapy for Neuro-Psychiatric-Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
John L
JL
Waddington
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D058068:Endophenotypes; D004843:Epistasis, Genetic; D005260:Female; D006120:Grooming; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009425:Nesting Behavior; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010121:Oxytocin / Q000378:metabolism; D065808:Prepulse Inhibition / Q000235:genetics; D011595:Psychomotor Agitation / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012919:Social Behavior; D014667:Vasopressins / Q000378:metabolism
D000662:Amphetamines; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D014667:Vasopressins; D010121:Oxytocin
endophenotypes; gene × gene interaction; genetic mouse model; psychosis