Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1.
Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across 2 different sites and protocols, Nrg1 mutants demonstrated deficits in prepulse inhibition, a measure of sensorimotor gating, that is, disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in a "what-where-when" object recognition memory task, Nrg1 mutants displayed sex-specific (males only) disruption of "what-when" performance, indicative of impaired temporal aspects of episodic memory. Differential metabolomic profiling revealed that these behavioral phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioral changes in adulthood.
School of Medicine, University College Cork, Cork, Ireland.
Colm M P
CMP
O'Tuathaigh
School of Psychology, University of Nottingham, Nottingham, UK.
Naina
N
Mathur
School of Psychology, University of Nottingham, Nottingham, UK.
Matthew J
MJ
O'Callaghan
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Lynsey
L
MacIntyre
Victor Chang Cardiac Research Institute, Sydney, Australia.
Richard
R
Harvey
Victor Chang Cardiac Research Institute, Sydney, Australia.
Donna
D
Lai
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, 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
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Benjamin S
BS
Pickard
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
David G
DG
Watson
School of Psychology, University of Nottingham, Nottingham, UK.
Paula M
PM
Moran
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D061212:Memory, Episodic; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D020890:Neuregulin-1 / Q000235:genetics*; D065808:Prepulse Inhibition / Q000187:drug effects / Q000502:physiology*; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D012737:Sex Factors
D014150:Antipsychotic Agents; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse
antipsychotics; choline; cognition; lipids; metabolome; mutant phenotype; neuregulin; prepulse inhibition; schizophrenia