Skip to main content

Research Repository

Advanced Search

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.

Authors

C.M.P. O'Tuathaigh

N. Mathur

M.J. O'Callaghan

L. MacIntyre

R. Harvey

D. Lai

J.L. Waddington

B.S. Pickard

D.G. Watson

Paula M. Moran



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 (OUP)
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 http://eprints.nottingham.ac.uk/id/eprint/39462
Publisher URL https://academic.oup.com/schizophreniabulletin/article-lookup/doi/10.1093/schbul/sbw189
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

Files


sbw189.pdf (343 Kb)
PDF

Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





You might also like



Downloadable Citations