title: Dysregulation of Specialized Delay/Interference-Dependent Working Memory Following Loss of Dysbindin-1A in Schizophrenia-Related Phenotypes.
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 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.
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Emilie I
authors.initials: EI
authors.lastname: Petit
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Michalak
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cox
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.|School of Medicine, University College Cork, Cork, Ireland.
authors.forename: Colm M P
authors.initials: CM
authors.lastname: O'Tuathaigh
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Office of Research and Innovation, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: Clarke
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Orna
authors.initials: O
authors.lastname: Tighe
authors.affiliation: Department of Neurology, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
authors.forename: Derek
authors.identifier: http://orcid.org/0000-0002-5005-4731
authors.initials: D
authors.lastname: Blake
authors.affiliation: Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.|Horizon Discovery, Cambridge, UK.
authors.forename: Josephine
authors.initials: J
authors.lastname: Joel
authors.affiliation: Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shaw
authors.affiliation: Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.|Takeda Cambridge, Cambridge, UK.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Sheardown
authors.affiliation: Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.|Worldwide Business Development, GlaxoSmithKline, Stevenage, UK.
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Morrison
authors.affiliation: Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.|Laboratory Animal Sciences, GlaxoSmithKline, Stevenage, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Shapland
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
authors.affiliation: Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
authors.forename: James N
authors.initials: JN
authors.lastname: Kew
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kirby
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Jiangsu Key Laboratory of Translational Research & Therapy for Neuro-Psychiatric-Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
mesh_terms: D000818:Animals; D001288:Attention / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology*; D004195:Disease Models, Animal; D000074765:Dysbindin / Q000502:physiology*; D005260:Female; D008297:Male; D057567:Memory, Long-Term / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D055696:Olfactory Perception / Q000502:physiology; D010641:Phenotype; D020033:Protein Isoforms; D012559:Schizophrenia / Q000503:physiopathology*
chemical_list: C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D020033:Protein Isoforms