Specialized information processing deficits and distinct metabolomic profiles following TM-domain disruption of Nrg1

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dc.contributor.author O'Tuathaigh, Colm M. P.
dc.contributor.author Mathur, Naina
dc.contributor.author O'Callaghan, Matthew J.
dc.contributor.author MacIntyre, Lynsey
dc.contributor.author Harvey, Richard P.
dc.contributor.author Lai, Donna
dc.contributor.author Waddington, John L.
dc.contributor.author Pickard, Benjamin S.
dc.contributor.author Watson, David G.
dc.contributor.author Moran, Paula M.
dc.date.accessioned 2017-03-24T13:03:39Z
dc.date.available 2017-03-24T13:03:39Z
dc.date.issued 2017-03-11
dc.identifier.citation 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. and Moran, p. M. (2017) ‘Specialized information processing deficits and distinct metabolomic profiles following TM-domain disruption of Nrg1’, Schizophrenia Bulletin, sbw189 (14pp). doi: 10.1093/schbul/sbw189 en
dc.identifier.startpage 1 en
dc.identifier.endpage 14 en
dc.identifier.issn 0586-7614
dc.identifier.uri http://hdl.handle.net/10468/3831
dc.identifier.doi 10.1093/schbul/sbw189
dc.description.abstract 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. en
dc.description.sponsorship Wellcome Trust (Grant Number WT0845921Z); Science Foundation Ireland (07/IN.1/B960) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Oxford University Press on behalf of the Maryland Psychiatric Research Center en
dc.rights © 2017, the Authors. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. en
dc.rights.uri http://creativecommons.org/licenses/by/4.0/ en
dc.subject Mutant phenotype en
dc.subject Cognition en
dc.subject Metabolome en
dc.subject Antipsychotics en
dc.subject Neuregulin en
dc.subject Prepulse inhibition en
dc.subject Choline en
dc.subject Lipids en
dc.subject Schizophrenia en
dc.title Specialized information processing deficits and distinct metabolomic profiles following TM-domain disruption of Nrg1 en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Colm Ó Tuathaigh, Medicine , University College Cork, Cork, Ireland. +353-21-490-3000 Email: c.otuathaigh@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder Wellcome Trust en
dc.contributor.funder Science Foundation Ireland en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Schizophrenia Bulletin en
dc.internal.IRISemailaddress c.otuathaigh@ucc.ie en
dc.identifier.articleid sbw189


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© 2017, the Authors. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Except where otherwise noted, this item's license is described as © 2017, the Authors. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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