Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease
Chun-Hwei Tai, Ya-Chin Yang, Ming-Kai Pan, Chen-Syuan Huang, Chung-Chin Kuo
Chun-Hwei Tai, Ya-Chin Yang, Ming-Kai Pan, Chen-Syuan Huang, Chung-Chin Kuo
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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 4

Attenuation of spontaneous burst and spiking discharges of STN by Ni2+, mibefradil, and NNC 55-0396 in acute slices.

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Attenuation of spontaneous burst and spiking discharges of STN by Ni2+, ...
Scale bar: 2 seconds, for all firing traces in this figure. (A) Left: 600 μM Ni2+ abolishes discharges in a cell that fires spontaneously in a burst mode. The effect of Ni2+ can be readily washed out by reperfusion of saline. The data in the boxed panel show that lower concentrations of Ni2+ (e.g., 200 μM) would attenuate bursts and turn the cell fired in a more spiking pattern. Right: The spontaneous spiking firing can also be inhibited by 600 μM Ni2+ and readily washed out by saline. The overall average spike frequency is robustly decreased by 600 μM Ni2+ (n = 5, **P < 0.005). (B) 50 μM mibefradil wipes out both burst and spiking discharges of STN. The data in the boxed panel show that 5 μM mibefradil turns the phasic bursts into spiking discharges. (C) 5–10 μM NNC 55-0396 shows effects similar to those of Ni2+ and mibefradil. The representative currents show inhibition of LVA currents (elicited at –40 mV from a holding potential of –120 mV) by 10 μM NNC 55-0396. Scale bars: 100 pA/2 ms.