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

PSYCHONEUROENDOCRINOLOGY

卷:38

Article

Trent, Simon^1,2,3,4,5,6  Dean, Rachel⁷  Veit, Bonnie⁷  Cassano, Tommaso⁸  Bedse, Gaurav⁹  Ojarikre, Obah A.¹⁰  Humby, Trevor^1,2,3,4,5,6  Davies, William^1,2,3,4,5,6 

[1] Cardiff Univ, Sch Psychol, Behav Genet Grp, Cardiff CF10 3AX, S Glam, Wales

[2] Cardiff Univ, Sch Psychol, Neurosci & Mental Hlth Res Inst, Cardiff CF10 3AX, S Glam, Wales

[3] Cardiff Univ, Sch Med, Behav Genet Grp, Cardiff CF10 3AX, S Glam, Wales

[4] Cardiff Univ, Sch Med, Neurosci & Mental Hlth Res Inst, Cardiff CF10 3AX, S Glam, Wales

[5] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales

[6] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales

[7] Cardiff Univ, Sch Psychol, Cardiff CF10 3AX, S Glam, Wales

[8] Univ Foggia, Sch Med, Dept Clin & Expt Med, Foggia, Italy

[9] Univ Roma La Sapienza, Dept Physiol & Pharmacol, I-00185 Rome, Italy

[10] MRC Natl Inst Med Res, Div Stem Cell Biol & Dev Genet, London, England

关键词: Acetylserotonin O-methyttransferase;    Attention deficit hyperactivity disorder;    Autism;    Dehydroepiandrosterone;    Hippocampus;    Locomotor activity;    Serotonin;    Spatial working memory;    Steroid sulfatase;    Xp22.3;   

DOI  :  10.1016/j.psyneuen.2012.12.002

来源: Elsevier

【 摘 要 】

Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,(XO)-O-Y. 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,(XO)-O-Y. 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,(XO)-O-Y. 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,(XO)-O-Y. 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,(XO)-O-Y. model. (C) 2012 Elsevier Ltd. All rights reserved.

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