title: Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.
abstract: Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)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,X(Y*)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,X(Y*)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,X(Y*)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,X(Y*)O model.
authors.affiliation: Behavioural Genetics Group and Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Trent
authors.forename: Rachel
authors.initials: R
authors.lastname: Dean
authors.forename: Bonnie
authors.initials: B
authors.lastname: Veit
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cassano
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bedse
authors.forename: Obah A
authors.initials: OA
authors.lastname: Ojarikre
authors.forename: Trevor
authors.initials: T
authors.lastname: Humby
authors.forename: William
authors.initials: W
authors.lastname: Davies
mesh_terms: D000121:Acetylserotonin O-Methyltransferase / Q000235:genetics*; D000818:Animals; D001070:Appetitive Behavior / Q000502:physiology*; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D003687:Dehydroepiandrosterone / Q000097:blood; D005106:Exploratory Behavior; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism; D006948:Hyperkinesis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007175:Impulsive Behavior / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D012701:Serotonin / Q000378:metabolism; D043266:Steryl-Sulfatase / Q000235:genetics*
chemical_list: D012701:Serotonin; D003687:Dehydroepiandrosterone; D000121:Acetylserotonin O-Methyltransferase; D043266:Steryl-Sulfatase