Regularizing firing patterns of rat subthalamic neurons ameliorates parkinsonian motor deficits
Qian-Xing Zhuang, … , Jian-Jun Wang, Jing-Ning Zhu
Qian-Xing Zhuang, … , Jian-Jun Wang, Jing-Ning Zhu
Published September 18, 2018
Citation Information: J Clin Invest. 2018;128(12):5413-5427. https://doi.org/10.1172/JCI99986.
View: Text | PDF
Research Article Neuroscience

Regularizing firing patterns of rat subthalamic neurons ameliorates parkinsonian motor deficits

Abstract

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.

Authors

Qian-Xing Zhuang, Guang-Ying Li, Bin Li, Chang-Zheng Zhang, Xiao-Yang Zhang, Kang Xi, Hong-Zhao Li, Jian-Jun Wang, Jing-Ning Zhu

×

Figure 7

Downregulation of HCN2 attenuates STN-DBS–induced amelioration of motor dysfunction, firing patterns, and β oscillations in free-moving PD rats.

Options: View larger image (or click on image) Download as PowerPoint
Downregulation of HCN2 attenuates STN-DBS–induced amelioration of motor ...
(A) Locomotor traces of PD rats in an open field. STN-DBS increased total movement distance of PD rats, whereas downregulation of HCN2 in STN abolished DBS-induced motor amelioration (n = 5). (B) STN-DBS increased histamine release in STN of PD rats in open field (n = 7). (C) Three continuous oscilloscope traces show firings of 3 STN neurons in free-moving PD rats treated with control virus, control virus plus STN-DBS, or downregulation of HCN2 virus plus STN-DBS. Red arrowheads indicate firing spikes of recorded STN neurons during DBS. Insets represent 5 superimposed traces of spike waveforms for each unit. (D–F) Autocorrelation histograms, scatter plots of ISI series, and ISI histograms of 3 STN neurons presented in C. (G and H) STN-DBS decreased CV of ISIs and number of bursts and increased interburst intervals of STN neurons in free-moving PD rats, whereas downregulation of HCN2 blocked STN-DBS–induced regularization of neuronal firing patterns (n = 15). (I) Power spectrograms of simultaneously recorded local field potentials in STN of these free-moving PD rats in the open field. (J) Power spectral distribution of local field potentials recorded from STN. Gray box indicates the classic β band (15–25 Hz). A clear increase of power in the β band was found in the PD rats. STN-DBS significantly alleviated dominant β band oscillatory activities in PD rats, whereas downregulation of HCN2 abolished STN-DBS–induced suppression of excessive β oscillations (n = 15). Data are represented as mean ± SEM. ***P < 0.001, 1-way ANOVA with Newman-Keuls post hoc test (A, G, H, and J) and 2-tailed paired t test (B).