Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism

Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
Cell (Impact Factor: 32.24). 07/2009; 137(7):1235-46. DOI: 10.1016/j.cell.2009.04.024
Source: PubMed


Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca(2+) responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.

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Available from: Kota Tamada, Sep 29, 2015
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    • "In vitro studies show that editing (Vitali et al., 2005) and splicing (Kishore & Stamm, 2006) of the Htr2c RNA are regulated by the snoRNA mbii52. Mouse models where mbii52 levels were either increased (Nakatani et al., 2009) or decreased (Doe et al., 2009) express higher levels of Htr2c editing. This suggests a dynamic interplay between mbii52 and the Htr2c RNA, and we therefore measured snoRNA levels when editing is blocked in our INI mice. "
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    ABSTRACT: The 5-hydroxytryptamine2C (5-HT)2C receptor is widely implicated in the aetiology of affective and eating disorders as well as regulation of the hypothalamo-pituitary-adrenal axis. Signalling through this receptor is regulated by A-to-I RNA editing, affecting three amino acids in the protein sequence, with unedited transcripts encoding a receptor (INI) that, in vitro, is hyperactive compared with edited isoforms. Targeted alteration (knock-in) of the Htr2c gene to generate ‘INI’ mice with no alternate splicing, solely expressing the full-length unedited isoform, did not produce an overt metabolic phenotype or altered anxiety behaviour, but did display reduced depressive-like and fear-associated behaviours. INI mice exhibited a hyperactive hypothalamo-pituitary-adrenal axis, with increased nadir plasma corticosterone and corticotrophin-releasing hormone expression in the hypothalamus but responded normally to chronic stress and showed normal circadian activity and activity in a novel environment. The circadian patterns of 5-HT2C receptor mRNA and mbii52, a snoRNA known to regulate RNA editing and RNA splicing of 5-HT2C receptor pre-mRNA, were altered in INI mice compared with wild-type control mice. Moreover, levels of 5-HT1A receptor mRNA were increased in the hippocampus of INI mice. These gene expression changes may underpin the neuroendocrine and behavioural changes observed in INI mice. However, the phenotype of INI mice was not consistent with a globally hyperactive INI receptor encoded by the unedited transcript in the absence of alternate splicing. Hence, the in vivo outcome of RNA editing may be neuronal cell type specific.
    European Journal of Neuroscience 09/2014; 40(11). DOI:10.1111/ejn.12727 · 3.18 Impact Factor
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    • "Early rodent studies showed that anxiolytics prevent decreases in social interaction that occur when animals are placed in anxiogenic environments (i.e., novel environments, bright light) (File et al., 1976; File and Hyde, 1978; File and Seth, 2003). Further, various autistic mouse models exhibit both pronounced deficits in sociability as well as enhanced anxiety-like behaviors (Nakatani et al., 2009; Silverman et al., 2010; Peça et al., 2011). In line with human literature, serotonin activity in rodents mediates social behaviors such as aggression and social reward (Saudou et al., 1994; Dölen et al., 2013), while reduced serotonin signaling increases anxiety (Heisler et al., 1998; Ramboz et al., 1998; Gross et al., 2002; Akimova et al., 2009). "
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    ABSTRACT: Many psychiatric illnesses are characterized by deficits in the social domain. For example, there is a high rate of co-morbidity between autism spectrum disorders and anxiety disorders. However, the common neural circuit mechanisms by which social deficits and other psychiatric disease states, such as anxiety, are co-expressed remains unclear. Here, we review optogenetic investigations of neural circuits in animal models of anxiety-related behaviors and social behaviors and discuss the important role of the amygdala in mediating aspects of these behaviors. In particular, we focus on recent evidence that projections from the basolateral amygdala (BLA) to the ventral hippocampus (vHPC) modulate anxiety-related behaviors and also alter social interaction. Understanding how this circuit influences both social behavior and anxiety may provide a mechanistic explanation for the pathogenesis of social anxiety disorder, as well as the prevalence of patients co-diagnosed with autism spectrum disorders and anxiety disorders. Furthermore, elucidating how circuits that modulate social behavior also mediate other complex emotional states will lead to a better understanding of the underlying mechanisms by which social deficits are expressed in psychiatric disease.
    Frontiers in Behavioral Neuroscience 07/2014; 8(241):1-14. DOI:10.3389/fnbeh.2014.00241 · 3.27 Impact Factor
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    • "Pups from dams exposed to a higher dose of FA during gestation and lactation made increased USVs as neonates; these behaviors may have originated from FA induced alteration of gene expression during the gestational period. Increased USVs have been found in mouse models for autism [33], [34]. Anxiety symptoms are highly prevalent in children with developmental disorders, including autism [35]. "
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    ABSTRACT: Background Studies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice. Methods Dams were fed FA either at 0.4 mg or 4 mg/kg diet throughout the pregnancy and the resulting pups were maintained on the diet throughout experimentation. Newborn pups brain cerebral hemispheres were used for microarray analysis. To confirm alteration of several genes, quantitative RT-PCR (qRT-PCR) and Western blot analyses were performed. In addition, various behavior assessments were conducted on neonatal and adult offspring. Results Results from microarray analysis suggest that the higher dose of FA supplementation during gestation alters the expression of a number of genes in the newborns’ cerebral hemispheres, including many involved in development. QRT-PCR confirmed alterations of nine genes including down-regulation of Cpn2, Htr4, Zfp353, Vgll2 and up-regulation of Xist, Nkx6-3, Leprel1, Nfix, Slc17a7. The alterations in the expression of Slc17a7 and Vgll2 were confirmed at the protein level. Pups exposed to the higher dose of FA exhibited increased ultrasonic vocalizations, greater anxiety-like behavior and hyperactivity. These findings suggest that although FA plays a significant role in mammalian cellular machinery, there may be a loss of benefit from higher amounts of FA. Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior.
    PLoS ONE 07/2014; 9(7):e101674. DOI:10.1371/journal.pone.0101674 · 3.23 Impact Factor
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