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

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Petit, Emilie I.
Michalak, Zuzanna
Cox, Rachel
O'Tuathaigh, Colm M. P.
Clarke, Niamh
Tighe, Orna
Talbot, Konrad
Blake, Derek
Joel, Josephine
Shaw, Alexander
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Nature Publishing Group
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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 long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A -/-showed enhancement in delay-dependent working memory under high levels of interference relative to controls, ie, 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.
Catechol-O-methyltransferase , Hilar mossy cells , Sdy mutant mice , Susceptibility gene , Sex-differences , Hippocampal-formation , Prefrontal cortex , Messenger-rna , Dentate gyrus , DTNBP1 gene
Petit, E. I., Michalak, Z., Cox, R., O’Tuathaigh, C. M. P., Clarke, N., Tighe, O., Talbot, K., Blake, D., Joel, J., Shaw, A., Sheardown, S. A., Morrison, A. D., Wilson, S., Shapland, E. M., Henshall, D. C., Kew, J. N., Kirby, B. P. and Waddington, J. L. (2016) 'Dysregulation of specialized delay/interference-dependent working memory following loss of dysbindin-1A in schizophrenia-related phenotypes', Neuropsychopharmacology, 42, pp. 1349–1360. doi: 10.1038/npp.2016.282
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© 2017, American College of Neuropsychopharmacology. All rights reserved. This is the Accepted Manuscript of an article published by Nature Publishing Group in Neuropsychopharmacology on 16th December, 2016, available online: https://doi.org/10.1038/npp.2016.282