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

项目总结 帕金森氏病(Parkinson‘s Disease，PD)可导致运动功能障碍，其原因是大脑 多巴胺能黑质纹状体通路和纹状体中多巴胺的丢失。这些病理变化改变了 神经元活动遍及基底节。其中一个显著的变化是，运动部的活动 苍白球内节段(GPI)的数目增加并异常图案化。目前可用的药物 或者，帕金森病症状的神经外科治疗经常受到不良副作用的阻碍 限制它们在患者中的使用。当前疗法的许多不良反应无疑是由于它们的不足造成的。 细胞或脑回路的特异性。可逆性调制选择性脑内神经元的微创方法 基底神经节运动区的运动方式可能为缓解帕金森病提供一种替代方法 没有副作用。我们假设，针对特定基因神经元的化学发生方法可能 成为一种更安全、至少同样有效的替代方案。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。然后，这些受体可以被系统性地激活 被管理的化合物，否则是惰性的。在计划中的实验中，我们将使用一种新的化学遗传学 基于受体调节的配基门控离子通道的表达，降低GPI活性的方法 用1-甲基-4-苯基-1，2，3，6-甲基-4-苯基-1，2，3，6-二甲基苯治疗稳定帕金森病的恒河猴 四氢吡啶(MPTP)。MPTP诱导的帕金森综合征的表型和生理相似性 而帕金森病使MPTP治疗的猴子成为这一目的的极好模型。我们有很强的初步结果 这表明我们计划使用的化学发生受体(“药理选择性激活分子”) (PSAM))可以利用病毒载体在猴的GPI神经元中成功表达，并且系统地 给予PSAM激活化合物可改善GPI活性，并伴随着 有动静。我们现在计划评估PSAM介导的MPTP中GPI失活的抗帕金森病效果。 已处理的猴子(目标1)。在这些实验过程中，我们将研究急性或慢性的影响 使用两种PSAM激活化合物(小剂量的varenicline，临床批准的吸烟 戒毒药物，或新产生的“药理选择性效应分子”(PSEM))。回应： 这些药物的疗效将与抗帕金森症的黄金标准药物左旋多巴进行比较。在AIM下 2，我们将检查PSAM在GPI中的表达模式和寿命，并将从组织学上验证 长期使用这些化学发生治疗方法不会产生可识别的神经毒性效应。这个 拟议的研究将帮助我们将PSAM方法开发为帕金森症的治疗方法，这可能会提供 与目前可用的治疗方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.