Regularizing firing patterns of rat subthalamic neurons ameliorates parkinsonian motor deficits
Regularizing firing patterns of rat subthalamic neurons ameliorates parkinsonian motor deficits
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调节大鼠丘脑底神经元的放电模式可改善帕金森运动缺陷
DOI：
10.1172/jci99986
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发表时间：
2018
影响因子：
15.9
通讯作者：
Zhu Jing-Ning
中科院分区：
文献类型：
--
作者：
Zhuang Qian-Xing;Li Guang-Ying;Li Bin;Zhang Chang-Zheng;Zhang Xiao-Yang;Xi Kang;Li Hong-Zhao;Wang Jian-Jun;Zhu Jing-Ning
丘脑底核（STN）是帕金森病（PD）深部脑刺激（DBS）的有效治疗靶点，PD患者基底神经节中的组胺水平升高。然而，内源性组胺能调节对 STN 神经元活动的影响以及 STN-DBS 背后的神经元机制尚不清楚。在这里，我们报告 STN 神经元放电模式比运动控制的放电率更重要。组胺兴奋 STN 神经元，但矛盾的是改善了帕金森运动缺陷，我们将其归因于通过与 H2 受体耦合的超极化激活的环核苷酸门控通道 2 (HCN2) 通道调节 STN 神经元的放电模式。有趣的是，DBS 增加了 STN 中的组胺释放，并在帕金森病条件下调节了 STN 神经元放电模式。 HCN2 有助于 DBS 诱导的神经元放电模式的调节、抑制过度的 β 振荡以及缓解 PD 中的运动缺陷。结果揭示了调节 STN 神经元放电模式在改善帕金森运动功能障碍和帕金森基底神经节回路中组胺的功能补偿中不可或缺的作用。这些发现提供了对 STN-DBS 机制以及 PD 潜在治疗靶点和 STN-DBS 策略的见解。
The subthalamic nucleus (STN) is an effective therapeutic target for deep brain stimulation (DBS) for Parkinson’s disease (PD), and histamine levels are elevated in the basal ganglia in PD patients. However, the effect of endogenous histaminergic modulation on STN neuronal activities and the neuronal mechanism underlying STN-DBS are unknown. Here, we report that STN neuronal firing patterns are more crucial than firing rates for motor control. Histamine excited STN neurons, but paradoxically ameliorated parkinsonian motor deficits, which we attributed to regularizing firing patterns of STN neurons via the hyperpolarization-activated cyclic nucleotide–gated channel 2 (HCN2) channel coupled to the H2 receptor. Intriguingly, DBS increased histamine release in the STN and regularized STN neuronal firing patterns under parkinsonian conditions. HCN2 contributed to the DBS-induced regularization of neuronal firing patterns, suppression of excessive β oscillations, and alleviation of motor deficits in PD. The results reveal an indispensable role for regularizing STN neuronal firing patterns in amelioration of parkinsonian motor dysfunction and a functional compensation for histamine in parkinsonian basal ganglia circuitry. The findings provide insights into mechanisms of STN-DBS as well as potential therapeutic targets and STN-DBS strategies for PD.