Elucidating the Role of Neuroactive Steroids in Tourette Syndrome

 描述(申请人提供)：多发性抽动症(TS)是一种神经发育障碍，以无目的和重复的运动为特征，定义为抽搐。大量研究表明，这些表现主要源于知觉缺陷，而这种缺陷通常会因压力而加剧。TS中最典型的知觉缺陷会影响感觉运动门控，这一功能旨在过滤来自无关外部刺激的显著感觉输入。在S患者和动物模型中，门控缺陷被测量为惊跳反射的脉冲前抑制(PPI)的减少，这包括微弱的前刺激减弱由响亮的爆发声引起的惊吓反应的能力。与多巴胺在TS发病机制中的关键作用一致，PPI通过激活小鼠中的多巴胺D1受体而减少。目前治疗TS的方法有时效果不佳，因为它们的目标是降低抽搐的严重性，而不是 潜在的知觉问题；此外，这些药物可能导致严重的运动和认知问题，从而极大地降低患者的依从性。我们研究的目标是了解TS知觉缺陷的神经生物学基础，并利用这些关键信息来确定更好的治疗方法。为此，我们课题组最近的研究发现，神经类固醇别孕酮(AP)及其生物合成酶5-α-还原酶(5-αR)可能是开发TS新疗法的最佳候选药物。事实上，临床研究表明，典型的5αR抑制剂非那雄胺显著降低成人TS患者的抽动严重程度，而不会引起明显的副作用。此外，该药物还可以减轻用D1受体激动剂治疗的小鼠的PPI缺陷。值得注意的是，AP是应激反应的主要调节器，并因急性应激而增加；因此，我们发现束缚应激也以时间依赖的方式扰乱小鼠的PPI。先前的研究表明，神经类固醇可能会干扰D1受体的信号转导。基于这一证据，我们假设：i)应激可能通过增加5αR水平和AP的合成来干扰PPI；ii)非那雄胺在PPI中的抗多巴胺能特性可能反映了AP合成的减少和D1受体信号的改变。我们将结合行为、药理学、神经化学和外科手术方法，在5只α还原酶基因敲除或野生型小鼠身上，从两个方面检验这一假说。我们的结果将有助于阐明神经类固醇调节TS知觉缺陷的神经生物学机制，并有助于确定这种疾病的新治疗靶点。

 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 5α-reductase (5αR) may be optimal candidates for the development of novel therapies for TS. Indeed, clinical studies have shown that the prototypical 5αR 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 5αR 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 5α-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.