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 1

Electrophysiological characterization of and effect of Ni2+ on LVA Ca2+ currents in acutely dissociated subthalamic neurons.

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Electrophysiological characterization of and effect of Ni2+ on LVA Ca2+ ...
(A) Representative “pure” voltage-dependent LVA Ca2+ currents recorded from a subthalamic neuron. The same neuron is stepped from a holding potential (Vh) of –120 mV or –70 mV to different test voltages (–100 to +60 mV) to elicit Ca2+ currents in the absence (control, black traces) or presence (blue traces) of 1 mM Ni2+. The HVA Ca2+ currents are apparently absent in this cell and in the recording condition. The current-voltage relationship of the shown currents is also plotted. Scale bars: 50 pA/20 ms for all traces in A. (B) LVA Ca2+ currents elicited at –50 mV from a holding potential of –120 mV are recorded in the absence (black traces) and presence (colored traces) of 30, 100, 300, or 1,000 μM Ni2+ in the same neuron. Two control currents (Control I and Control II) were obtained before and after application of different concentrations of Ni2+. The average Ni2+ inhibitory effect on LVA Ca2+ currents is plotted on the right. The curve is a fit based on a one-to-one binding reaction and is of the form: relative inhibition = ([Ni2+]/175 μM)/[1 + ([Ni2+]/175 μM)]. n = 4, 5, 6, and 4 for 30, 100, 300, and 1,000 μM Ni2+, respectively. Scale bars: 25 pA/5 ms.