Elucidating the Role of Neuroactive Steroids in Tourette Syndrome

University Of Kansas Lawrence, Lawrence KS

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Abstract

? DESCRIPTION (provided by applicant): Tourette syndrome (TS) is a neurodevelopmental disorder featuring purposeless and repetitive movements defined as tics. Ample research has shown that these manifestations are primarily rooted in perceptual deficits, which are typically exacerbated by stress. The best-characterized perceptual deficit in TS affects sensorimotor gating, the function aimed at filtering salient sensory input from irrelevant external stimuli. In S patients and animal models, gating deficits are measured as a reduction of prepulse inhibition (PPI) of the startle reflex, which consists in the ability of a weak prestimulus to attenuate the startle response elicited by a loud burst. In keeping with the key role of dopamine in TS pathogenesis, PPI is reduced by activation of dopamine D1 receptors in mice. Current therapies for TS are sometimes poorly effective, in that they are aimed at reducing tic severity, rather than the underlying perceptual problems; furthermore, these drugs can lead to severe motor and cognitive problems, which greatly reduce patient compliance. The goal of our research is to understand the neurobiological bases of the perceptual deficits in TS and use this critical information to identify better therapies. To this end, the research of our group has recently identified that the neurosteroid allopregnanolone (AP), and its biosynthetic enzyme 5?-reductase (5?R) may be optimal candidates for the development of novel therapies for TS. Indeed, clinical studies have shown that the prototypical 5?R inhibitor finasteride markedly reduces tic severity in adult TS patients, without causing overt side effects. Furthermore, this drug attenuates the PPI deficits in mice treated with D1 receptor agonists. Notably, AP is a major modulator of stress response and is increased by acute stress; accordingly, we found that restraint stress also disrupted PPI in mice in a time-dependent fashion. Previous studies have shown that neurosteroids may interfere with D1 receptor signaling. Building on this evidence, we hypothesize that: i) stress may disrupt PPI by enhancing 5?R levels and AP synthesis; and ii) the antidopaminergic properties of finasteride in PPI may reflect the reduced synthesis of AP and alterations of D1 receptor signaling. We will test the hypothesis in two aims, using a combination of behavioral, pharmacological, neurochemical and surgical approaches on 5?-reductase knockout or wild-type mice. Our results will help elucidate the neurobiological mechanisms by which neurosteroids may regulate perceptual deficits in TS, and lead to the identification of novel therapeutic targets for this disorder.