title: Altered serotonergic function may partially account for behavioral endophenotypes in steroid sulfatase-deficient mice.
abstract: The X-linked gene STS encodes the steroid hormone-modulating enzyme steroid sulfatase. Loss-of-function of STS, and variation within the gene, have been associated with vulnerability to developing attention deficit hyperactivity disorder (ADHD), a neurodevelopmental condition characterized by inattention, severe impulsivity, hyperactivity, and motivational deficits. ADHD is commonly comorbid with a variety of disorders, including obsessive-compulsive disorder. The neurobiological role of steroid sulfatase, and therefore its potential role in ADHD and associated comorbidities, is currently poorly understood. The 39,X(Y)*O mouse, which lacks the Sts gene, exhibits several behavioral abnormalities relevant to ADHD including inattention and hyperactivity. Here, we show that, unexpectedly, 39,X(Y)*O mice achieve higher ratios than wild-type mice on a progressive ratio (PR) task thought to index motivation, but that there is no difference between the two groups on a behavioral task thought to index compulsivity (marble burying). High performance liquid chromatography analysis of monoamine levels in wild type and 39,X(Y)*O brain tissue regions (the frontal cortex, striatum, thalamus, hippocampus, and cerebellum) revealed significantly higher levels of 5-hydroxytryptamine (5-HT) in the striatum and hippocampus of 39,X(Y)*O mice. Significant correlations between hippocampal 5-HT levels and PR performance, and between striatal 5-HT levels and locomotor activity strongly implicate regionally-specific perturbations of the 5-HT system as a neurobiological candidate for behavioral differences between 40,XY and 39,X(Y)*O mice. These data suggest that inactivating mutations and functional variants within STS might exert their influence on ADHD vulnerability, and disorder endophenotypes through modulation of the serotonergic system.
authors.affiliation: Behavioral Genetics Group, Schools of Medicine and Psychology, Cardiff University, Cardiff, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Trent
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: D000161:Acoustic Stimulation / Q000379:methods; D000367:Age Factors; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D058068:Endophenotypes; D005106:Exploratory Behavior / Q000502:physiology; D016114:Ichthyosis, X-Linked / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D012054:Reinforcement, Psychology; D012701:Serotonin / Q000378:metabolism*; D018709:Statistics, Nonparametric; D043266:Steryl-Sulfatase / Q000235:genetics*
chemical_list: D015306:Biogenic Monoamines; D012701:Serotonin; D043266:Steryl-Sulfatase