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 2

Effect of mibefradil (green traces) and Ni2+ (blue traces) on Ca2+ and Na+ currents in dissociated STN neurons.

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Effect of mibefradil (green traces) and Ni2+ (blue traces) on Ca2+ and N...
The holding potential is –120 mV. (A) Representative currents show that 3 μM mibefradil dramatically inhibits the Ca2+ current elicited at –60 mV (left panel) but has little inhibitory effect on that elicited at +30 mV (middle panel) in the same neuron. The peak LVA Ca2+ current amplitude (elicited at –60 mV) in the presence of drug is normalized to that in control to give the average inhibitory effect of 1–10 μM mibefradil (right panel, n = 4). Scale bars: 20 pA/20 ms. (B) 300 μM Ni2+ and 3 μM mibefradil lack an effect on subthalamic neuronal Na+ currents that are either elicited at 0 mV (and abolished by 300 nM TTX; left panel) or elicited at –40 mV (middle panel). In this experiment, the external TEA-based solution is replaced by a low-calcium Tyrode’s solution (see Methods). The Na+ current (elicited at 0 mV) in the presence of drug is normalized to that in control to show the average drug effects (right panel, each n = 4). The dashed line indicates zero current level. Scale bars: 500 pA/0.5 ms. (C) Inhibition of LVA Ca2+ currents by 300 μM Ni2+ and 3 μM mibefradil with the addition of 300 nM TTX in the external TEA-based solution. The normalized Ca2+ current to the control is plotted to show the averaged effects (right panel, n = 4). The box shows the same inhibition of LVA currents by Ni2+ and mibefradil if 5 mM Ca2+ is replaced by 5 mM Ba2+ in the external TEA-based solution. Scale bars: 50 pA/20 ms.