Steroid sulfatase-deficient mice exhibit endophenotypes relevant to Attention Deficit Hyperactivity Disorder

Abstract

SummaryAttention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition characterised by inattention, impulsivity and hyperactivity; it is frequently co-morbid with anxiety and conduct disorders, sleep perturbation and abnormal consummatory behaviours. Recent studies have implicated the neurosteroid-modulating enzyme steroid sulfatase (STS) as a modulator of ADHD-related endophenotypes. The effects of steroid sulfatase deficiency on homecage activity, feeding/drinking behaviours, anxiety-related behaviours (assayed in light-dark box and open field paradigms), social dominance and serum steroid hormone levels were determined by comparing 40,XY and 39,XY*O mice. Subsequently, mice administered the steroid sulfatase inhibitor COUMATE acutely were compared to vehicle-treated mice on behavioural tasks sensitive to enzyme deficiency to dissociate between its developmental and ongoing effects. 39,XY*O mice exhibited heightened reactivity to a novel environment, hyperactivity in the active phase, and increased water (but not food) consumption relative to 40,XY mice during a 24 h period; the former group also demonstrated evidence for heightened emotional reactivity. There was no difference in social dominance between the 40,XY and 39,XY*O mice. COUMATE administration had no effect on homecage activity, water consumption or anxiety measures in the open field. 39,XY*O mice exhibited significantly lower dehydroepiandrosterone (DHEA) serum levels than 40,XY mice, but equivalent corticosterone levels. Together with previous data, the present results suggest that steroid sulfatase may influence core and associated ADHD behavioural endophenotypes via both developmental and ongoing mechanisms, and that the 39,XY*O model may represent a useful tool for elucidating the neurobiological basis of these endophenotypes.

Polymorphisms of STS gene and SULT2A1 gene and neurosteroid levels in Han Chinese boys with attention-deficit/hyperactivity disorder: an exploratory investigation

“…The 5-CSRTT, a rodent analogue of the human CPT, is a laboratory behavioral task for assessing neurobiological substrates of attention56. Therefore, compatible with our findings, previous data in mice have suggested a link between attention and DHEA(S) levels921222324. The protective effects of DHEA(S) on patients’ neuropsychological function may account for enhancing neuron growth5, regulating GABA A and NMDA activity67, or modulating the complex process of cortical maturation during middle childhood5758.…”

“…Several animal studies have revealed that the 39,X(Y)*O mice with deletion of the STS gene exhibit abnormal behaviors and cognitive functions that are relevant to the inattention and hyperactivity that many ADHD patients experience2122. The ADHD-like features seemed to be correlated with the dysregulation of steroid hormone levels and neurotransmitters2324, and improvement may be triggered through administration with DHEA-S25.…”

Mouse model systems to study sex chromosome genes and behavior: Relevance to humans

“…Results from the 39,X Y* O males were similar to those obtained in females, showing deficits in attention, further implicating Sts (Davies et al , 2009). More recent studies have expanded on those findings, by showing that X Y* O males are hyperactive as compared to XY males and they display increased anxiety in a light-dark box (Trent et al , 2012). However, no direct comparisons have been made between males and females of the Y* cross to determine which other factors, such as gonadal hormones and Y chromosome effects, may also influence attention.…”

Are ASD and ADHD a Continuum? A Comparison of Pathophysiological Similarities Between the Disorders

“…Humans with STS deficiency are at significantly increased risk of developing ADHD-I and ASD (Kent et al, 2008;Trent et al, 2012).…”