Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
Department of Developmental Neurobiology and Neurophysiology, Neurobiology Institute, National Autonomous University of Mexico, Queretaro, Mexico.
Elife. 2019 Apr 24;8:e40818. doi: 10.7554/eLife.40818.
Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD.
亨廷顿病（HD）最初的特征是无法抑制不想要的运动，这种缺陷归因于纹状体间接通路棘突投射神经元（iSPNs）的突触激活受损。为了更好地理解这种缺陷的机制，使用电生理、光学和生化方法研究了来自亨廷顿病小鼠遗传模型的离体脑片的纹状体神经元。来自有症状的 HD 小鼠的 iSPNs 的远端树突兴奋性降低，这种变化归因于树突 Kv4 钾通道与辅助 KChIP 亚基的关联增加。这种关联受 TrkB 受体信号的负调节。通过敲低 Kv4 通道的表达、破坏 KChIP 结合、恢复 TrkB 受体信号或用锌指蛋白降低突变型-Htt（mHtt）水平，可挽救 HD iSPNs 的树突兴奋性。总之，这些研究表明，mHtt 诱导 iSPNs 的树突兴奋性的可逆改变，这可能导致 HD 的运动症状。
