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,XY*O mouse, which lacks the Sts gene, exhibits several behavioral abnormalities relevant to ADHD including inattention and hyperactivity. Here, we show that, unexpectedly, 39,XY*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,XY*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,XY*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,XY*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.
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Acknowledgements
The study was funded by a Medical Research Council United Kingdom (MRC, UK) New Investigator Grant to WD (91052), by a Research Councils UK Fellowship to WD and by grant PRIN 2009 to TC. We would like to thank Dr Silvana Gaetani in whose laboratory the neurochemical analyzes were conducted.
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Trent, S., Cassano, T., Bedse, G. et al. Altered Serotonergic Function may Partially Account for Behavioral Endophenotypes in Steroid Sulfatase-deficient Mice. Neuropsychopharmacol 37, 1267–1274 (2012). https://doi.org/10.1038/npp.2011.314
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DOI: https://doi.org/10.1038/npp.2011.314
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