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

dc.contributor.authorO'Tuathaigh, Colm M. P.
dc.contributor.authorMathur, Naina
dc.contributor.authorO'Callaghan, Matthew J.
dc.contributor.authorMacIntyre, Lynsey
dc.contributor.authorHarvey, Richard P.
dc.contributor.authorLai, Donna
dc.contributor.authorWaddington, John L.
dc.contributor.authorPickard, Benjamin S.
dc.contributor.authorWatson, David G.
dc.contributor.authorMoran, Paula M.
dc.contributor.funderWellcome Trusten
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2017-03-24T13:03:39Z
dc.date.available2017-03-24T13:03:39Z
dc.date.issued2017-03-11
dc.description.abstractAlthough 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.sponsorshipWellcome Trust (Grant Number WT0845921Z); Science Foundation Ireland (07/IN.1/B960)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleidsbw189
dc.identifier.citationO’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/sbw189en
dc.identifier.doi10.1093/schbul/sbw189
dc.identifier.endpage14en
dc.identifier.issn0586-7614
dc.identifier.journaltitleSchizophrenia Bulletinen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/3831
dc.language.isoenen
dc.publisherOxford University Press on behalf of the Maryland Psychiatric Research Centeren
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.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectMutant phenotypeen
dc.subjectCognitionen
dc.subjectMetabolomeen
dc.subjectAntipsychoticsen
dc.subjectNeuregulinen
dc.subjectPrepulse inhibitionen
dc.subjectCholineen
dc.subjectLipidsen
dc.subjectSchizophreniaen
dc.titleSpecialized information processing deficits and distinct metabolomic profiles following TM-domain disruption of Nrg1en
dc.typeArticle (peer-reviewed)en
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