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

Simon Trent,Rachel Dean,Bonnie Veit,Gaurav Bedse,Trevor Humby,Obah A Ojarikre,Tommaso Cassano,William Davies

doi:10.1016/j.psyneuen.2012.12.002

Abstract

SummaryChromosomal 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.

Highlights

Pathogenic cytogenetic deletions within Xp22.3 are relatively common in patients with autistic spectrum disorders (ASDs) (Thomas et al, 1999; Chocholska et al, 2006; Vorstman et al, 2006; Kent et al, 2008; Shinawi et al, 2009), characterised by social/communication impairments, restricted interests or repetitive/stereotyped behaviours, hyperactivity and anxiety (O’Hare, 2009)
Xp22.3 deletions have been reported in cases of attention deficit hyperactivity disorder (ADHD) (Boycott et al, 2003; Lonardo et al, 2007; Kent et al, 2008), a second neurodevelopmental condition characterised by inattention, pathological impulsivity and hyperactivity (Thapar et al, 2012) which is commonly comorbid with autism and which is thought to share overlapping genetic aetiology (Rommelse et al, 2010); individuals with ADHD may display a heightened tendency towards behavioural perseveration (Fischer et al, 2005; Tsuchiya et al, 2005)
Several Xp22.3 genes represent good candidates for conferring vulnerability to psychiatric illness: functional mutations within NLGN4X have been reported in cases of autism (Jamain et al, 2003; Laumonnier et al, 2004), whilst mutations within ASMT have been seen in individuals with autism (Melke et al, 2008; Jonsson et al, 2010) and ADHD (Chaste et al, 2011)

Summary

Introduction

Pathogenic cytogenetic deletions within Xp22.3 are relatively common in patients with autistic spectrum disorders (ASDs) (Thomas et al, 1999; Chocholska et al, 2006; Vorstman et al, 2006; Kent et al, 2008; Shinawi et al, 2009), characterised by social/communication impairments, restricted interests or repetitive/stereotyped behaviours, hyperactivity and anxiety (O’Hare, 2009). Xp22.3 deletions have been reported in cases of attention deficit hyperactivity disorder (ADHD) (Boycott et al, 2003; Lonardo et al, 2007; Kent et al, 2008), a second neurodevelopmental condition characterised by inattention, pathological impulsivity and hyperactivity (Thapar et al, 2012) which is commonly comorbid with autism and which is thought to share overlapping genetic aetiology (Rommelse et al, 2010); individuals with ADHD may display a heightened tendency towards behavioural perseveration (Fischer et al, 2005; Tsuchiya et al, 2005). Cytogenetic deletions encompassing STS (encoding the enzyme steroid sulfatase (Sts)) and inactivating mutations/genetic variants within the gene can influence ADHD risk and presentation (Kent et al, 2008; Stergiakouli et al, 2011). Understanding how lack of the gene products above impacts upon neurobiology and behaviour will be important for illuminating the pathophysiological basis of multiple psychiatric conditions

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