Histamine Regulation of the Basal Ganglia and the Pathophysiology of Tics

摘要 抽动秽语综合征(TS)和其他抽动障碍影响多达5%的人口，并经常合并 有其他神经精神疾病。他们的神经生物学知之甚少，目前的治疗方法是 常常是无效的。最近的遗传学发现表明组胺(HA)信号调节失调是一种罕见的 原因：在最近发表在《神经元》上的一篇论文中，我们建立了HA缺陷型组氨酸脱羧酶(HDC)基因敲除 小鼠作为抽动症病理生理学的模型，具有病因学、面孔和预测有效性。 一致的证据表明抽动障碍中存在皮质-基底节回路。特别是，监管失调 纹状体中的多巴胺(DA)被认为是一个重要的促成因素。透明质酸受体高度 在基底节环路中表达。HA调节纹状体DA水平：野生型HA输注 小鼠体内纹状体DA减少，HA缺陷的HDC-KO模型基础DA水平升高。在我们的 首先，我们将阐明这种鲜为人知的监管相互作用的机制。我们假设 HA作用于黑质致密部(SNC)抑制性中间神经元上的H1R受体。 我们将使用体内药理学和微透析来测试这一点。然后我们将测试必要性和充分性 使用一种新的化学发生策略，研究HA诱导的SNC神经元间活动对纹状体DA调节的影响。 在HDC-KO抽动模型中，基线DA失调和重复的行为病理是微妙的，但它们是 由于行为或药理上的干扰而显著增加。例如，压力会导致重复 模型中的行为。纹状体内神经元的局部去抑制产生未见的DA的显著尖峰 在WT动物身上。这表明DA动态平衡的丧失，使系统处于相态不稳定-a 类似抽动障碍的阶段现象学的模式。我们假设H1R音调的丧失 SNC中间神经元移除了一个自我平衡调节的来源；我们将在我们的第二个目标中测试这一点。 我们发现，在化学遗传学沉默HA神经元后，我们发现了更戏剧性的重复行为病理 在活体内。这表明，缓解机制约束了KO动物的行为病理。 确定这种机制具有基本和翻译两方面的重要性；加强这些机制可以 代表了一种新的治疗策略，在抽动障碍和其他高多巴胺能病理中都是如此。我们 我将在目标3中对这一观察到的两种可能的解释之间进行仲裁。 在急性沉默HA神经元后会更加深刻，因为它还扰乱了GABA的共同传递，这是 在KO动物体内完好无损。其次，KO动物可能会对个体发育产生补偿。我们将使用 结合化学遗传学和shRNA敲除来检验这两个假说。 从长远来看，这一创新研究计划具有基础和翻译两方面的重要性，旨在 阐明透明质酸在基底节中的正常作用，确定其扰动如何导致抽动，并确定 潜在的新治疗目标。

ABSTRACT Tourette syndrome (TS) and other tic disorders affect up to 5% of the population and are frequently comorbid with other neuropsychiatric conditions. Their neurobiology is poorly understood, and current treatments are often inefficacious. Recent genetic findings implicate dysregulation of histamine (HA) signaling as a rare cause; in a recent paper in Neuron we established the HA-deficient histidine decarboxylase (Hdc) knockout mouse as a model of tic pathophysiology that has etiologic, face, and predictive validity. Convergent evidence implicates the cortico-basal ganglia circuitry in tic disorders. In particular, dysregulation of dopamine (DA) in the striatum is thought to be an important contributing factor. HA receptors are highly expressed in the basal ganglia circuitry. HA regulates DA levels in the striatum: HA infusion in a wild-type mouse reduces striatal DA in vivo, and the HA-deficient Hdc-KO model has elevated basal DA levels. In our first Aim we will elucidate the mechanisms of this poorly understood regulatory interaction. We hypothesize that HA acts on H1R receptors found on inhibitory interneurons in the substantia nigra pars compacta (SNc). We will test this using in vivo pharmacology and microdialysis. We will then test the necessity and sufficiency of HA-induced SNc interneuronal activity for striatal DA regulation, using a novel chemogenetic strategy. Baseline DA dysregulation and repetitive behavioral pathology in the Hdc-KO tic model are subtle, but they are dramatically increased by behavioral or pharmacological perturbations. For example, stress induces repetitive behaviors in the model. Local neuronal disinhibition in the striatum produces a dramatic spike in DA, not seen in WT animals. This suggests a loss of DA homeostasis, rendering the system subject to phasic instability – a pattern that resembles the phasic phenomenology of tic disorders. We hypothesize that loss of H1R tone on SNc interneurons removes a source of homeostatic regulation; we will test this in our second Aim. We find much more dramatic repetitive behavioral pathology after HA neurons are chemogenetically silenced in vivo. This suggests that mitigating mechanisms constrain behavioral pathology in the KO animal. Identification of such mechanisms is of both basic and translational importance; enhancing them may represent a novel therapeutic strategy, both in tic disorders and in other hyperdopaminergic pathologies. We will arbitrate between two possible explanations for this observation in Aim #3. First, behavioral pathology may be more profound after acute silencing of HA neurons because it also disrupts GABA cotransmission, which is intact in the KO animals. Second, KO animals may develop compensations over ontogeny. We will use a combination of chemogenetics and shRNA knockdown to test these two hypotheses. In the long term, this innovative research program is of both basic and translational importance, aiming to elucidate the normal role of HA in the basal ganglia, establish how its perturbation can lead to tics, and identify potential new treatment targets.