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Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder

Trent, Simon, Dean, Rachel, Veit, Bonnie, Cassano, Tommaso, Bedse, Gaurav, Ojarikre, Obah A., Humby, Trevor and Davies, William 2013. Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder. Psychoneuroendocrinology 38 (8) , pp. 1370-1380. 10.1016/j.psyneuen.2012.12.002

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Abstract

Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,XY*O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,XY*O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,XY*O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a ‘foraging’ task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or ‘ability to wait’, it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,XY*O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,XY*O model.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology
Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: Acetylserotonin O-methyltransferase; Attention deficit hyperactivity disorder; Autism; Dehydroepiandrosterone; Hippocampus; Locomotor activity; Serotonin; Spatial working memory; Steroid sulfatase; Xp22.3
Publisher: Elsevier
ISSN: 0306-4530
Funders: MRC
Date of First Compliant Deposit: 30 March 2016
Last Modified: 02 May 2019 13:08
URI: http://orca.cf.ac.uk/id/eprint/43679

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