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Dysregulation of specialized delay/interference-dependent working memory following loss of Dysbindin-1A in schizophrenia-related phenotypes

Petit, Emilie I, Michalak, Zuzanna, Cox, Rachel, O'Tuathaigh, Colm M P, Clarke, Niamh, Tighe, Orna, Talbot, Konrad, Blake, Derek J., Joel, Josephine, Shaw, Alexander, Sheardown, Steven A, Morrison, Alastair D, Wilson, Stephen, Shapland, Ellen M, Henshall, David C, Kew, James N, Kirby, Brian P and Waddington, John L 2017. Dysregulation of specialized delay/interference-dependent working memory following loss of Dysbindin-1A in schizophrenia-related phenotypes. Neuropsychopharmacology 42 (6) , pp. 1349-1360. 10.1038/npp.2016.282

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Abstract

Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B and C) remain unknown, we generated a novel mutant mouse, dys-1A-/-, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin-1A was not associated with disruption of either longterm (olfactory) memory or spontaneous alternation behavior. However, dys-1A-/- showed enhancement in delay-dependent working memory under high levels of interference relative to controls, i.e. impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A-/- provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Publisher: Nature Publishing Group
ISSN: 0893-133X
Date of First Compliant Deposit: 18 May 2017
Date of Acceptance: 17 September 2016
Last Modified: 04 Jun 2018 19:12
URI: http://orca-mwe.cf.ac.uk/id/eprint/100668

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