Characterising a newly-identified modulator of ADHD risk: the behavioural and neural functions of steroid sulfatase

Children with Attention Deficit Hyperactivity Disorder (or ADHD as it is more commonly known) have trouble concentrating, are hyperactive and often act without giving due thought to the consequences of their actions. Moreover, they are often anxious, aggressive and have problems sleeping. Consequently, they often have difficulties regarding education and social interactions, which can cause substantial and deleterious knock-on effects on their adult lives.
Many studies have shown that ADHD risk has a strong genetic basis. Interestingly, ADHD seems to affect boys far more commonly than girls, implying that one or more genes on the X or Y chromosomes may influence vulnerability to developing the disorder. Recent work in mice and in humans has identified one gene on the X chromosome which may influence this vulnerability. The gene is called STS, and when it is absent boys (or mice) are prone to developing symptoms associated with ADHD. The protein made by the STS gene is called steroid sulfatase. Currently, little is known about the role steroid sulfatase plays in the brain, and in particular, how it might act to influence attention and impulsivity. As experiments on human brain function are difficult to perform and limited in their scope, the present proposal will use mice to identify the effects of steroid sulfatase manipulation on brain development and function, with a view to characterising the function of the protein. These experiments should give us important clues as to what is going wrong in the brains of subjects with ADHD, an essential first step to working out how we might remedy it. The results obtained from our studies might also ultimately help us to develop therapies against other common and debilitating disorders associated with attention and impulsivity problems, including autism and schizophrenia.

Attentional dysfunction and response control deficits are hallmarks of many common neuropsychiatric disorders, including Attention Deficit Hyperactivity Disorder (ADHD). ADHD is a childhood-onset, highly disabling and disruptive neurodevelopmental condition, characterised by inattention, impulsiveness and hyperactivity; it is often comorbid with anxiety, sleep and conduct/oppositional defiant disorders. The disorder has a strong underlying genetic component, and the fact that it is sexually dimorphic in its incidence and presentation, suggests a modulatory role for one or more sex-linked genes on risk. We have previously shown that the enzyme steroid sulfatase, a modulator of neuroactive steroids, encoded by the X-linked gene Sts can influence the major ADHD endophenotypes of attention and impulse control in mice. Parallel human work has shown that subjects with deletions of the STS gene are at significantly elevated ADHD risk, and that certain STS polymorphisms may predispose to ADHD vulnerability.
The purpose of the present proposal is: i) to characterise the specificity and extent to which aberrant steroid sulfatase function may contribute to symptoms associated with ADHD, particularly the core deficits in response control, using elegant pharmacological and genetic mouse models and ii) to exploit the neurobiological tractability of the same models to identify neurochemical/genetic changes elicited by acute and developmental manipulations of the steroid sulfatase axis which may underlie any Sts-dependent effects on behaviour.
The proposed work will increase our knowledge about the function of steroid sulfatase in the mammalian brain, and will therefore allow us novel insights into the biological mechanisms through which steroid sulfatase dysfunction may predispose to behavioural and cognitive abnormalities in disorders such as ADHD. Ultimately, the work could improve ADHD diagnosis and indicate novel targets for more effective therapies.