Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease
Chun-Hwei Tai, … , Chen-Syuan Huang, Chung-Chin Kuo
Chun-Hwei Tai, … , Chen-Syuan Huang, Chung-Chin Kuo
Published July 1, 2011
Citation Information: J Clin Invest. 2011;121(8):3289-3305. https://doi.org/10.1172/JCI46482.
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Research Article Neuroscience

Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease

Abstract

An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca2+ channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca2+ channels reduces motor deficits in a rat model of PD. Ni2+, mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca2+ currents in acutely dissociated STN neurons, but not Cd2+ and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca2+ currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca2+ channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd2+ and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca2+ channels. We therefore conclude that modulation of subthalamic T-type Ca2+ currents and consequent burst discharges may provide new strategies for the treatment of PD.

Authors

Chun-Hwei Tai, Ya-Chin Yang, Ming-Kai Pan, Chen-Syuan Huang, Chung-Chin Kuo

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Figure 7

Increased in vivo burst discharges of STN in parkinsonian rats.

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Increased in vivo burst discharges of STN in parkinsonian rats. In total...
In total, 26 single units of STN neurons were recorded in 3 normal rats, and 53 single units were recorded in 6 parkinsonian rats. (A) Tyrosine hydroxylase immunohistochemistry of brain sections from normal and parkinsonian rats. Note the severe loss of dopaminergic cells in the SNc (left panels, arrowheads) and the striatum (right panels, arrows) after unilateral lesion by 6-OHDA (lower panels) compared with the control group (upper panels). (B) Representative in vivo recordings from STN in parkinsonian rats showing spiking (tonic, upper trace), burst (phasic, middle trace), and mixed (lower trace) types of firing. (C) Detected spikes were sorted with the PCA algorithm. The inset shows the morphology of spikes in each selected single unit (red or green) and unselected spikes (white). (D) Burst detection parameters used for the single-unit spike trains. A trace of STN single-unit recording (top) with raster of sorted spikes (middle) and the result of burst detection (bottom) is shown as an example. See Methods for details. (E) There are more STN neurons firing in the burst mode in the parkinsonian rats (n = 53) than in the control group (n = 26). The percentage of neurons that are free of burst firing is markedly lower in the parkinsonian group (11.1%) than in the control (normal) group (35.5%). (F) The burst counts in the 30-second recording session increase significantly in the parkinsonian rats. (G) The inter-burst interval is significantly shortened in the parkinsonian rats. Scale bars: 2 seconds and 10 ms for B and D, respectively. **P < 0.01, normal versus parkinsonian rats.