Altered serotonergic function may partially account for behavioral endophenotypes in steroid sulfatase-deficient mice

Neuropsychopharmacology. 2012 Apr;37(5):1267-74. doi: 10.1038/npp.2011.314. Epub 2011 Dec 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation / methods
  • Age Factors
  • Animals
  • Biogenic Monoamines / metabolism
  • Brain / metabolism*
  • Chromatography, High Pressure Liquid
  • Disease Models, Animal
  • Endophenotypes*
  • Exploratory Behavior / physiology
  • Ichthyosis, X-Linked / genetics
  • Ichthyosis, X-Linked / metabolism*
  • Ichthyosis, X-Linked / pathology
  • Ichthyosis, X-Linked / physiopathology*
  • Mice
  • Reinforcement, Psychology
  • Serotonin / metabolism*
  • Statistics, Nonparametric
  • Steryl-Sulfatase / genetics*


  • Biogenic Monoamines
  • Serotonin
  • Steryl-Sulfatase