Specialised information processing deficits and distinct metabolomics profiles following TM-domain disruption of Nrg1

O'Tuathaigh, C.M.P.; Mathur, N.; O'Callaghan, M.J.; MacIntyre, L.; Harvey, R.; Lai, D.; Waddington, J.L.; Pickard, B.S.; Watson, D.G.; Moran, Paula M.

Abstract

© The Author 2017. 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.

Citation

O'Tuathaigh, C., Mathur, N., O'Callaghan, M., MacIntyre, L., Harvey, R., Lai, D., …Moran, P. M. (2017). Specialised information processing deficits and distinct metabolomics profiles following TM-domain disruption of Nrg1. Schizophrenia Bulletin, 43(5), 1100-1113. https://doi.org/10.1093/schbul/sbw189

• Journal Article Type: Article
• Acceptance Date: Nov 29, 2016
• Online Publication Date: Mar 11, 2017
• Publication Date: Sep 1, 2017
• Deposit Date: Dec 20, 2016
• Publicly Available Date: Mar 11, 2017
• Journal: Schizophrenia Bulletin
• Print ISSN: 0586-7614
• Electronic ISSN: 1745-1701
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 43
• Issue: 5
• Pages: 1100-1113
• DOI: https://doi.org/10.1093/schbul/sbw189
• Keywords: Mutant Phenotype, Cognition, Metabolome, Antipsychotics, Neuregulin, Pre-pulse inhibition, Choline, Lipids, Schizophrenia
• Public URL: https://nottingham-repository.worktribe.com/output/849695
• Publisher URL: https://academic.oup.com/schizophreniabulletin/article-lookup/doi/10.1093/schbul/sbw189