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.

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

“…Initial phenotypic characterization showed sexually dimorphic phenotypes, with female knockouts (KO) being more reactive to stressful situations and male KO showing increased exploration during initial exposure to a novel environment that may be related to some disruption in habituation and dysregulation of hippocampus-dependent working memory function. No effect of genotype was observed during acquisition or during performance in long-term (olfactory) memory or either a conventional spatial working memory task (spontaneous alternation) or a low-interference delay-dependent working memory task; however, in a highinterference task variant, male KO mutants showed impairment in vulnerability to interference (Petit et al, 2017).…”

“…We have recently described the generation of a genetic mouse model with isoform-specific deletion of dysbindin-1A protein (Petit et al, 2017). Initial phenotypic characterization showed sexually dimorphic phenotypes, with female knockouts (KO) being more reactive to stressful situations and male KO showing increased exploration during initial exposure to a novel environment that may be related to some disruption in habituation and dysregulation of hippocampus-dependent working memory function.…”

Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC‐1 and BORC complexes

“…In fact, genetic association studies show that DTNBP1 polymorphisms influence cognitive and neuroanatomical traits in humans (Ghiani and Dell'angelica, ; Mullin et al, ; Papaleo et al, ). Moreover, mouse and Drosophila dysbindin mutants have pronounced neurological, behavioral, learning, plasticity, and synaptic phenotypes (Cox et al, ; Dickman and Davis, ; Talbot et al, ; Tang et al, ; Carlson et al, ; Ghiani and Dell'angelica, ; Karlsgodt et al, ; Shao et al, ; Gokhale et al, ; Mullin et al, ; Petit et al, ). Although the human genetic association data are compelling arguments against subunits of the BLOC‐1 complex, we believe that, particularly with dysbindin, its status as a risk factor for psychotic disorders is more nuanced, as we describe below.…”

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies

“…Phenotypic studies conducted in mice mutant for dysbindin‐1 have revealed cognitive deficits, particularly in the domain of working memory, relative to wild‐type controls, although the expression and/or magnitude of these deficits varies depending on genetic background (Takao et al, ; Papaleo et al , ; Petit et al , ). In sdy mutants (containing a deletion mutation in the gene encoding dysbindin‐1) on a DBA background, male homozygous mice demonstrated deficits in long‐term memory (assessed in the Barnes maze), as well as spatial working memory (T‐maze, forced alternation task), in the absence of any genotypic differences across non‐cognitive domains.…”

“…In a more recent study examining the effect of selective deletion of the dysbindin‐1A subtype on schizophrenia‐related measures, no genotypic differences were observed during acquisition or during performance in a low‐interference working memory task (DNMP procedure). However, in a high‐interference variant of the DNMP procedure, male homozygous mutants demonstrated impairment in sensitivity to interference (Petit et al, ). Taken together, these data suggest working memory deficits in dysbindin‐1 mutants; such deficits appear to vary depending on behavioural parameters and involve separate or combined effects of modification of D 2 receptors and glutamatergic processes (Papaleo and Weinberger, ).…”