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Deficit of long-term memory retention in sdy mice. (A) Latency to reach the target hole (up), numbers of errors (middle) and distance to reach the target hole (bottom) across training were recorded. Data were analyzed by two-way repeated measures ANOVA. Data are presented as averages of 3 trials. (B) Time spent around each hole in the probe trial conducted 24 hours after last training. (C) Time spent around each hole in the probe trial conducted 7 days after last training. Time spent around target hole and holes adjacent to the target were compared by paired t-test.
Source publication
Schizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. The dystrobrevin-binding protein 1 (DTNBP1: dysbindin-1) gene is a major susceptibility gene for schizophrenia. Genetic variations in DTNBP1 are associated with cognitive functions, general cognitive ability and memory function, and clinical features o...
Citations
... These models can be broadly categorized into genetic (G) and environmental (E) models. Genetic models of representative genes associated with schizophrenia development, including disrupted-in-schizophrenia 1, neuregulin 1, and dystrobrevin-binding protein 1 gene-deficient mice [3][4][5][6] . Environmental models, on the other hand, are generated by exposing animals to factors known to induce schizophrenia-like symptoms, such as the administration of psychotomimetic substances like phencyclidine (PCP), amphetamine, and MK-801, or through isolation stress [7][8][9][10] . ...
The interactions between genetic and environmental factors (G x E interactions) play a crucial role in the pathogenesis of schizophrenia. The administration of phencyclidine, a psychotropic drug, to Kpna1-deficient mice induces behavioral abnormalities resembling schizophrenia. In the nucleus accumbens of these mice, the expressions of dopamine receptors, an RNA editing enzyme, and cytoplasmic dynein demonstrate gene-environment interaction-dependent alterations. Kpna1-deficient mice may be useful as a gene-environment interaction model for schizophrenia and provide insights into its pathogenesis. Further, changes in gene expression in the nucleus accumbens may be involved in the development of schizophrenia.
... Unlike other mutant mice, dysbindin deficient mutant mice showed increased basal startle and PPI responses, reversible by quinpirole (a dopamine D2 receptor agonist) (Papaleo et al., 2012). Dysbindin mutant mouse models have altered working memory measured as increased performance in spatial T-maze paradigm but impaired performance during a discrete paired-trial task under stress (Papaleo et al., 2012), reduced social interaction , impaired spatial reference memory and novel object recognition, and enhanced contextual fear conditioning (Arguello & Gogos, 2010;Bhardwaj et al., 2009;Feng et al., 2008;Takao et al., 2008). Sdy mice have reduced levels of snapin protein that is involved in neurotransmitter release , which may explain the abnormal schizophrenia-like behaviors observed in the mice and provide insight on the etiology of schizophrenia. ...
Genome-wide association studies have implicated microRNA-137 (miR-137) as a genetic susceptibility factor for schizophrenia. Individuals with risk alleles for single nucleotide polymorphisms (SNPs) in this gene have increased symptom severity, cognitive deficits, structural and functional brain changes associated with schizophrenia. Maternal immune activation (MIA) has also been implicated as an environmental risk factor affecting neurodevelopmental disorders such as schizophrenia. Since schizophrenia is thought to result from the combination of susceptibility genotypes and environmental risk factors, we assessed the gene-environment interaction between maternal immune activation and transgenic mice that carry the miR137 rs2660304 SNP. We phenotyped the behaviour of these mice and observed an exacerbation of spatial working memory deficits in the Y-Maze by MIA in female mutant mice. No major behavioral changes were found in the open field, social interaction and prepulse inhibition assessments. Decreased performance in the Y-Maze was accompanied by exacerbation of parvalbumin-positive interneuron deficits in the dentate gyrus of female mutant mice by maternal immune activation. This thesis work demonstrated a gene-environment interaction between a miR-137 and MIA in our animal model.
... Of particular interest is that dysbindin-1 modulates copper transporters and thus copper levels via the dysbindin/BLOC-1-copper metabolism interactome (Gokhale et al. 2015;Mullin et al. 2011;Warde-Farley et al. 2010). Knockout of dysbindin-1 in mice results in schizophrenia-like cognitive impairments, such as impaired long term, working, and spatial memory (Cox et al. 2009;Feng et al. 2008;Papaleo et al. 2012;Takao et al. 2008). Dysbindin-1 knockout mice also exhibit 30-50% lower copper transporters ATP7A and SLC31A1, which produce the proteins ATP7A and CTR1, respectively (Gokhale et al. 2015); together, ATP7A and CTR1 facilitate copper transport into the central nervous system (Eisses and Kaplan 2005;Scheiber et al. 2010;Yamaguchi et al. 1996). ...
Schizophrenia susceptibility factor dysbindin-1 is associated with cognitive processes. Downregulated dysbindin-1 expression is associated with lower expression of copper transporters ATP7A and CTR1, required for copper transport to the central nervous system. We measured dysbindin-1 isoforms-1A and -1BC, CTR1, and ATP7A via Western blots of the postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects (n = 28) and matched controls (n = 14). In addition, we subdivided the schizophrenia group by treatment status and comorbidity of alcohol use disorder (AUD) and assessed the relationships between proteins. Schizophrenia subjects exhibited similar protein levels to that of controls, with no effect of antipsychotic treatment. We observed a shift towards more dysbindin-1A expression in schizophrenia, as revealed by the ratio of dysbindin-1 isoforms. Dysbindin-1A expression was negatively correlated with ATP7A in schizophrenia, with no correlation present in controls. AUD subjects exhibited less dysbindin-1BC and CTR1 than those without AUD. Our results, taken together with previous data, suggest that alterations in dysbindin-1 and copper transporters are brain-region specific. For example, protein levels of ATP7A, dysbindin 1BC, and CTR1 are lower in the substantia nigra in schizophrenia subjects. AUD in the DLPFC was associated with lower protein levels of dysbindin-1 and CTR1. Changes in dysbindin-1 isoform ratio and relationships appear to be prevalent in the disease, potentially impacting symptomology.
... Genetic mouse models have been used to elucidate the selective contributions of dysbindin-1 and its isoforms to the emergence of schizophrenia-related phenotypes. Initial phenotypic studies conducted in mice mutant for all three isoforms of dysbindin-1 have revealed cognitive deficits, particularly in the domain of working memory, although the magnitude of these phenotypes can vary depending on factors including genetic background, environmental considerations, and paradigmatic differences [16][17][18]. Additionally, various hypotheses have been advanced to explain the mechanistic basis of the association between dysbindin-1 and cognitive dysfunction, including modification of dopamine D2 receptor, glutamatergic, and GABAergic processes [17,19]. ...
Dysbindin-1 is implicated in several aspects of schizophrenia, including cognition and both glutamatergic and dopaminergic neurotransmission. Targeted knockout of dysbindin-1A (Dys-1A KO), the most abundant and widely expressed isoform in the brain, is associated with deficits in delay/interference-dependent working memory. Using an ethologically based approach, the following behavioural phenotypes were examined in Dys-1A KO mice: exploratory activity, social interaction, anxiety and problem-solving ability. Levels of monoamines and their metabolites were measured in striatum, hippocampus and prefrontal cortex using high-performance liquid chromatography with electrochemical detection. The ethogram of initial exploration in Dys-1A KO mice was characterised by increased rearing from a seated position; over subsequent habituation, stillness was decreased relative to wildtype. In a test of dyadic social interaction with an unfamiliar conspecific in a novel environment, female KO mice showed an increase in investigative social behaviours. Marble burying behaviour was unchanged. Using the puzzle-box test to measure general problem-solving performance, no effect of genotype was observed across nine trials of increasing complexity. Dys-1A KO demonstrated lower levels of 5-HT in ratio to its metabolite 5-HIAA in the prefrontal cortex. These studies elaborate the behavioural and neurochemical phenotype of Dys-1A KO mice, revealing subtle genotype-related differences in non-social and social exploratory behaviours and habituation of exploration in a novel environment, as well as changes in 5-HT activity in brain areas related to schizophrenia.
... A considerable number of behavioral tests have been constructed to mimic human behaviors for application to translational research (Takahashi et al., 1994;Bućan and Abel, 2002;Takao et al., 2008;Yamasaki et al., 2008;Matsuo et al., 2009;Nakatani et al., 2009). Our results suggest that desflurane may have no or less postanesthetic behavioral effects in humans up to 7 days after anesthesia. ...
Halogenated ethers, such as desflurane, sevoflurane, and isoflurane, are known to exert an array of effects besides sedation. However, the postanesthetic effects of desflurane remain undiscovered as no study has explored these effects systematically. Phenotypic screening using behavioral test batteries is a powerful method to identify such effects. In the present study, we behaviorally phenotyped desflurane-treated mice to investigate postanesthetic effects. We applied comprehensive behavioral test batteries measuring sensorimotor functions, anxiety, depression, sociability, attention, and learning abilities, starting 7 days after anesthesia performed with 8.0% desflurane for 6 h. Although our previous study revealed postanesthetic effects of isoflurane in adult mice, in the current study, desflurane-treated mice exhibited no such effects in any behavioral test. To further examine whether desflurane affect behavior in more early time point, we built up a new additional test battery, which carried out 1 day or 3 days after exposure to desflurane. Mice treated with desflurane 1 day before testing showed more slips than other two groups in the first trial, suggesting mild acute side effects of desflurane on motor coordination. These results suggest the safety of desflurane in clinical settings and imply that postanesthetic effects are unique to each halogenated ether.
... These authors also confirmed a previous finding of direct interaction with and decrease in the steady-state level of snapin (a SNAP-25 binding protein), suggesting an upstream regulatory role of dysbindin on neurotransmitter release via snapin. Takao et al. (2008) also reported cognitive deficits, including impairment in long-term memory retention (Barnes maze test) and in working memory (T-maze, forced alternation task). Bhardwaj et al. (2009) also demonstrated deficits in shortterm memory (object recognition memory test) and stronger dependent memory for fearful events in sdy/DBA mice. ...
Alongside positive and negative symptomatology, deficits in working memory, attention, selective learning processes, and executive function have been widely documented in schizophrenia spectrum psychosis. These cognitive abnormalities are strongly associated with impairment across multiple function domains and are generally treatment-resistant. The DTNBP1 (dystrobrevin-binding protein-1) gene, encoding dysbindin, is considered a risk factor for schizophrenia and is associated with variation in cognitive function in both clinical and nonclinical samples. Downregulation of DTNBP1 expression in dorsolateral prefrontal cortex and hippocampal formation of patients with schizophrenia has been suggested to serve as a primary pathophysiological process. Described as a “hub,” dysbindin is an important regulatory protein that is linked with multiple complexes in the brain and is involved in a wide variety of functions implicated in neurodevelopment and neuroplasticity. The expression pattern of the various dysbindin isoforms (-1A, -1B, -1C) changes depending upon stage of brain development, tissue areas and subcellular localizations, and can involve interaction with different protein partners. We review evidence describing how sequence variation in DTNBP1 isoforms has been differentially associated with schizophrenia-associated symptoms. We discuss results linking these isoform proteins, and their interacting molecular partners, with cognitive dysfunction in schizophrenia, including evidence from drosophila through to genetic mouse models of dysbindin function. Finally, we discuss preclinical evidence investigating the antipsychotic potential of molecules that influence dysbindin expression and functionality. These studies, and other recent work that has extended this approach to other developmental regulators, may facilitate identification of novel molecular pathways leading to improved antipsychotic treatments.
... Whereas hallucinations and delusions are difficult to investigate in mice, the study of various genetic models helped identify key behavioral markers [49]. In addition to novelty-induced hyperactivity, Scn2a KO/+ mice displayed an increase in contextual fear memory consolidation and a deficit in locomotor coordination resembling the sdy dysbindin mutant mice [54][55][56]. Though milder than the spectrum of social deficits reported in other SCZ models [49], we observed a decrease in social behavior approach coupled with an experience-dependent social dominance in Scn2a KO/+ mice. ...
... In the present study, contextual fear learning was enhanced and the extinction of fear-related memory decreased in Scn2a KO/+ mice. Similar results have been reported in models of ASD [60] and SCZ [54,55]. Fear-related behavior relies on a complex network involving amygdala and the medial prefrontal cortex (mPFC) [61,62]. ...
Background
Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated.
Methods
We investigated the behavior of mice with a conventional or conditional deletion of Scn2a in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice.
Results
Conventional heterozygous Scn2a knockout mice (Scn2aKO/+) displayed novelty-induced exploratory hyperactivity and increased rearing. The increased vertical activity was reproduced by heterozygous inactivation of Scn2a in dorsal-telencephalic excitatory neurons but not in inhibitory neurons. Moreover, these phenotypes were rescued by treating Scn2aKO/+ mice with CX516. Additionally, Scn2aKO/+ mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2aKO/+ mice, with an increase in the gamma band.
Conclusions
Scn2aKO/+ mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes.
Electronic supplementary material
The online version of this article (10.1186/s13229-019-0265-5) contains supplementary material, which is available to authorized users.
... Furthermore, the identification of dysbindin as a susceptible gene for schizophrenia has gained much attention on the neuronal roles of BLOC-1 (Straub et al. 2002). Consistently, mice deficient in dysbindin or pallidin exhibit impaired working memory and social interactions, which are consistent with cognitive functions impaired in schizophrenia patients (Takao et al. 2008;Bhardwaj et al. 2009;Cox et al. 2009;Jentsch et al. 2009;Karlsgodt et al. 2011;Glen et al. 2014;Spiegel et al. 2015). In neurons, BLOC-1 is implicated in the biogenesis and release of synaptic vesicles in presynaptic terminals (Newell-Litwa et al. 2009;Di Giovanni and Sheng 2015;Chen et al., 2017). ...
... working memory and social interactions, which are consistent with the neurobehavioral phenotypes of animal models of schizophrenia (Takao et al. 2008;Bhardwaj et al. 2009;Cox et al. 2009;Jentsch et al. 2009;Karlsgodt et al. 2011;Glen et al. 2014;Spiegel et al. 2015). Therefore, it would be interesting to test the possibility that disturbance in the crosstalk between the cytohesin-2-Arf pathway and BLOC-1 in endosomal trafficking may contribute to the pathogenesis of neurodevelopmental disorders. ...
Cytohesin‐2 is a member of the guanine nucleotide exchange factors for ADP ribosylation factor 1 (Arf1) and Arf6, which are small GTPases that regulate membrane traffic and actin dynamics. In this study, we first demonstrated that cytohesin‐2 localized to the plasma membrane and vesicles in various subcellular compartment in hippocampal neurons by immunoelectron microscopy. Next, to understand the molecular network of cytohesin‐2 in neurons, we conducted yeast two‐hybrid screening of brain cDNA libraries using cytohesin‐2 as bait and isolated pallidin, a component of the biogenesis of lysosome‐related organelles complex 1 (BLOC‐1) involved in endosomal trafficking. Pallidin interacted specifically with cytohesin‐2 among cytohesin family members. GST pull‐down and immunoprecipitation assays further confirmed the formation of a protein complex between cytohesin‐2 and pallidin. Immunofluorescence demonstrated that cytohesin‐2 and pallidin partially colocalized in various subsets of endosomes immunopositive for EEA1, syntaxin 12, and LAMP2 in hippocampal neurons. Knockdown of pallidin or cytohesin‐2 reduced cytoplasmic EEA1‐positive early endosomes. Furthermore, knockdown of pallidin increased the total dendritic length of cultured hippocampal neurons, which was rescued by co‐expression of wild‐type pallidin but not a mutant lacking the ability to interact with cytohesin‐2. In contrast, knockdown of cytohesin‐2 had the opposite effect on total dendritic length. The present results suggested that the interaction between pallidin and cytohesin‐2 may participate in various neuronal functions such as endosomal trafficking and dendritic formation in hippocampal neurons.
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... Forced alternation task using the T-maze were performed as previously described with modifications [73,74]. The apparatus was constructed of white plastics runways with walls 25-cm high (O'Hara & Co., Tokyo) ( Fig 8J). ...
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.
... DTNBP1 binds to dystrobrevins, components of the dystrophin-associated glycol-protein complex (DGC), and is thought to play a fundamental role in regulating synaptic structure and signaling (Benson et al., 2001). Dtnbp1 deletion mice on a DBA/2J background strain were found to have increased anxiety and impaired social interaction, as well as deficits in working and recognition memory ( Hattori et al., 2008;Takao et al., 2008). These mice also displayed increased freezing response to a conditioned stimulus, suggesting deficits in emotional and motivated learning and memory (Bhardwaj et al., 2009). ...
The goal of this dissertation is to further understand the genetic architecture of neuropsychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia (SCZ). We attempt to understand the functional significance of the gene synapse associated protein of 97KDa (SAP97) and identify a novel role for SAP97 in the etiology of neuropsychiatric disorders.^ SAP97 belongs to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), that are highly enriched in the postsynaptic density of synapses and play an important role in organizing protein complexes necessary for synaptic development and plasticity. Large-scale genetic studies have implicated MAGUKs in neuropsychiatric disorders such as intellectual disability, ASD, and SCZ, but knock-out mice have been impossible to study because the Sap97 null mice die soon after birth due to a craniofacial defect. In Chapter 2, we studied the transcriptomic and behavioral consequences of a viable, brain-specific conditional knockout of Sap97 (SAP97-cKO). RNA sequencing (RNAseq) from hippocampi from control and SAP97-cKO male animals identified 67 differentially expressed transcripts, which were specifically enriched for SCZ-related genes. Subjecting SAP97-cKO mice to a battery of behavioral tests revealed a subtle anxiety-like phenotype present in both male and female SAP97-cKO animals, as well as a mild male-specific cognitive deficit and female-specific motor learning deficit. Collectively, this work suggests that loss of Sap97 alters behavior, and may contribute to some of the endophenotypes present in SCZ. In Chapter 3, we discuss how the SAP97-cKO mouse may serve as a novel model system for interrogating aspects of the cellular and molecular defects underlying SCZ and other related neuropsychiatric disorders.
