Optogenetic control of striatal dopamine in Huntington's disease

描述（由申请人提供）：亨廷顿氏病（HD）是一种遗传性常染色体神经退行性疾病，通常是致命的，并且没有有效的治疗或治愈方法。携带该突变的患者表现为运动功能障碍、认知障碍和精神障碍。神经病理学上，HD的特征是纹状体和皮层的神经元丢失，以及皮层和纹状体之间的逐渐断开，中断了从皮层到基底神经节的信息流。我们在两种全长HD转基因小鼠模型中发现，直接和间接纹状体输出通路突触活动的不平衡在疾病的早期和晚期有所不同，并导致运动症状。在HD早期，直接通路中型棘神经元（MSNs）上谷氨酸和GABA释放增加，而GABA释放在晚期增加，但仅在间接通路的MSNs上释放。突触活动的变化与早期HD小鼠重复行为的增加和晚期小鼠运动能力的下降有关。早期变化可能由纹状体多巴胺（DA）升高介导，因为内源性DA的消耗减少了重复行为并逆转了一些电生理改变。相反，HD晚期运动能力下降可能是由DA功能下降介导的。本应用程序的目标是采用新的光遗传学方法，使用光刺激激活和/或抑制HD小鼠模型中的DA终端，以更好地了解电生理和行为功能障碍。在Aim 1中，我们将利用光遗传学技术，通过在DA神经元中表达盐视紫红质（在黄光激活时抑制放电），选择性地抑制早期HD患者纹状体中的DA释放。在第二项研究中，我们将利用光遗传学技术，通过表达通道视紫红质（在蓝光激活时增加放电），选择性地增加晚期HD患者纹状体中DA的释放。我们假设减少早期HD的纹状体DA释放将恢复msn的突触活性，并将对异常的重复运动产生有益的影响。在晚期HD，增加DA释放将恢复MSN活动的部分平衡，并将减轻运动症状。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a genetic autosomal neurodegenerative disorder that is always fatal and for which there are no effective treatments or cures. Patients carrying the mutation display motor dysfunction, cognitive impairment and psychiatric disturbances. Neuropathologically, HD is characterized by neuronal loss in the striatum and cortex and a progressive disconnection between cortex and striatum, interrupting the flow of information from the cortex to the basal ganglia. We have shown that imbalances in synaptic activity in the direct and indirect striatal output pathways differ during early and late stages of the disease and contribute to motor symptoms in two full-length transgenic mouse models of HD. In early stage HD, there is increased glutamate and GABA release onto direct pathway medium-sized spiny neurons (MSNs) while GABA release is increased in the late stage but only onto indirect pathway MSNs. Changes in synaptic activity are associated with increased repetitive behaviors in early stage HD mice and with decreased locomotion in late stage mice. Early stage changes may be mediated by elevated striatal dopamine (DA), because depletion of endogenous DA reduced repetitive behaviors and reversed some of the electrophysiological alterations. In contrast, decreased locomotion in late stage HD might be mediated by decreased DA function. The goal of this application is to employ novel optogenetic approaches, using light stimulation to activate and/or inhibit DA terminals in a mouse model of HD, to better understand the electrophysiological and behavioral dysfunctions. In Aim 1 we will selectively inhibit DA release in the striatum in early stage HD, using optogenetics by expressing halorhodopsin (which inhibits firing when activated by yellow light) in DA neurons. In Aim 2 we will selectively increase DA release in the striatum in late stage HD using optogenetics by expressing channel rhodopsin (which increases firing when activated with blue light). We hypothesize that reducing striatal DA release in early stage HD will restore synaptic activity of MSNs and will have beneficial effects on abnormal repetitive movements. In late stage HD, increasing DA release will restore some of the balance in MSN activity and will alleviate motor symptoms. PUBLIC HEALTH RELEVANCE: In Huntington's disease, abnormal striatal dopamine transmission induces time-dependent alterations in excitatory and inhibitory synaptic transmission that contribute to imbalances in activity of the direct and indirect striatal output pathways leading to motor and cognitive disturbances. In order to modify the differential symptoms in early and late stages of Huntington's disease, this application will alter dopamine release using novel optogenetic approaches to uncover new targets to alleviate symptoms and slow the progression of this devastating genetic disorder.