Chemogenetic Inactivation of the Primate Internal Globus Pallidus as a treatment for Parkinsonism

项目摘要 帕金森氏病（PD）导致致残性运动障碍，其由帕金森氏病（PD）的退化引起。 多巴胺能黑质纹状体通路和纹状体中多巴胺的损失。这些病理变化改变了 整个基底神经节的神经元活动。其中一个显著的变化是运动部分的活动 苍白球内段（GPi）的增加和异常模式。目前可用的药物 或神经外科治疗PD的症状是阻碍不必要的副作用， 限制其在患者中的使用。目前治疗的许多副作用无疑是由于缺乏 细胞或脑回路的特异性。可逆性调节神经元的微创方法， 在基底神经节运动区域的方式可以提供一种替代方法来缓解帕金森症 没有副作用。我们假设，针对遗传特异性神经元的化学遗传学方法可能 是一个更安全，至少同样有效的替代品。化学发生技术涉及表达（通过 病毒载体）在特定神经元中的人工受体。这些受体可以被激活， 给药的化合物在其他方面是惰性的。在计划的实验中，我们将使用一种新的化学遗传学 一种基于受体调节的配体门控离子通道表达的方法， 通过用1-甲基-4-苯基-1，2，3，6-三氟甲基苯甲酸酯治疗已使恒河猴稳定帕金森病， 四氢吡啶（MPTP）。MPTP诱导的帕金森综合征的表型和生理相似性 和PD使MPTP处理的猴子成为用于此目的的极好模型。我们有很强的初步结果 表明我们计划使用的化学发生受体（“药理学选择性致动分子”） （PSAMs））可以使用病毒载体在猴的GPi神经元中成功表达，并且系统性地 施用PSAM活化化合物改善GPi活性，伴随着 运动我们现在计划评估PSAM介导的MPTP中GPi失活的抗帕金森病作用。 治疗的猴子（目标1）。在这些实验过程中，我们将研究急性或慢性 施用两种PSAM激活化合物（低剂量的伐尼克兰，临床上批准的吸烟疗法）， 终止药物，或新产生的“药物选择性效应分子”（PSEM））。的答复 将这些药物与金标准抗帕金森病药物左旋多巴进行比较。在aim下 2，我们将检查GPi中PSAM表达的模式和寿命，并将从组织学上证实 这些化学发生治疗方法的长期使用不具有可识别的神经毒性作用。的 拟议的研究将有助于我们将PSAM方法发展为帕金森症的治疗方法， 与目前可用的疗法相比具有显著的优势。

PROJECT SUMMARY Parkinson’s disease (PD) leads to disabling motor impairments, resulting from the degeneration of the dopaminergic nigrostriatal pathway and a loss of dopamine in the striatum. These pathological changes alter the neuronal activity throughout the basal ganglia. One of the salient changes is that the activity in the motor portion of the internal pallidal segment (GPi) is increased and abnormally patterned. The currently available medication or neurosurgical treatments for the symptoms of PD are encumbered by unwanted side effects that frequently limit their use in patients. Many of the adverse effects of the current therapies undoubtedly result from their lack of cellular or brain circuit specificity. Minimally invasive methods to reversibly modulate neurons in a selective manner in the motor territory of the basal ganglia could provide an alternative approach to alleviate parkinsonism without side effects. We hypothesize that chemogenetic methods that target genetically specified neurons may be a safer, and at least equally effective alternative. Chemogenetic techniques involve the expression (through viral vectors) of artificial receptors in specific neurons. These receptors can then be activated by systemically administered compounds that are otherwise inert. In the planned experiments, we will use a novel chemogenetic approach, based on the expression of receptor-modulated ligand-gated ion channels, to reduce GPi activity in rhesus monkeys that have been rendered stably parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). The phenotypic and physiologic similarities between MPTP-induced parkinsonism and PD make the MPTP-treated monkey an excellent model for this purpose. We have strong preliminary results indicating that the chemogenetic receptors we plan to use (“Pharmacologically selective actuator molecules” (PSAMs)) can be successfully expressed in GPi neurons of monkeys using viral vectors, and that systemic administration of PSAM-activating compounds ameliorate GPi activity, with accompanying changes in movement. We now plan to evaluate the antiparkinsonian effects of PSAM-mediated inactivation of GPi in MPTP- treated monkeys (aim 1). In the course of these experiments, we will study the effects of acute or chronic administration of two PSAM-activating compounds (low doses of varenicline, a clinically approved smoking cessation drug, or a newly generated “pharmacologically selective effector molecule” (PSEM)). The responses to these drugs will be compared to those of the gold-standard antiparkinsonian medication, levodopa. Under aim 2, we will examine the pattern and longevity of the PSAM expression in the GPi and will histologically verify that chronic use of these chemogenetic therapeutic methods do not have identifiable neurotoxic effects. The proposed studies will help us to develop the PSAM approach into a treatment for parkinsonism, that could offer notable advantages over the currently available therapies.