Genetic and Pharmacological Modulation of the Steroid Sulfatase Axis Improves Response Control; Comparison with Drugs Used in ADHD

Abstract

Maladaptive response control is a feature of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,X(Y*)O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. While the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent.

Impulsive choices in mice lacking imprinted Nesp55

“…2a, main effect of GENOTYPE, F 1,27 = 0.58, P = 0.45). The lack of differences in impulsive behaviour in this task was further demonstrated by another measure of response inhibition, the speed of stopping or SSRT derived, as is conventional (Bari et al 2009;Davies et al 2014;Humby et al 2013), in sessions where the subjects exhibited 50% correct stopping. Equivalent SSRTs were observed in both Nesp m/+ and control mice ( Fig.…”

Reversal learning performance in the XY* mouse model of Klinefelter and Turner Syndromes

“…Nevertheless, dysregulation of Sts in 40, XXY mice may still occur (e.g., due to skewed X-inactivation – X vs. X Y* – and/or escape from inactivation). Interest in STS as a contributor to phenotypic features of KS remains high because of previous studies in mice (Davies et al, 2009, 2014), and because of the association of STS with cognitive function and deficits in humans (Cavenagh et al, 2019; Chatterjee et al, 2016; Kent et al, 2008; Stergiakouli et al, 2011).…”

Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank

“…A study of female carriers revealed a comparable suite of behavioural differences from control subjects, together with an increased likelihood of postpartum depression 6. The pattern of behavioural phenotypes seen in males with XLI/carrier females overlaps with that seen in STS-deficient mice,13–17 and may therefore be largely ascribed to biological effects of STS deficiency rather than ascertainment or socialisation effects. Previous behavioural phenotyping approaches in XLI have been suboptimal: a) survey-based studies did not collect genetic data and so could not objectively confirm or define STS deletion carrier status, and these studies may theoretically have elicited responses from more severely affected individuals inflating risk estimates, b) only relatively early age points have been assessed (average age <45 years) and c) studies have had either no control group, or no contemporaneously recruited control group.…”