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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 Ca(2+) channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca(2+) channels reduces motor deficits in a rat model of PD. Ni(2+), mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca(2+) currents in acutely dissociated STN neurons, but not Cd(2+) and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca(2+) currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca(2+) channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd(2+) 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 Ca(2+) channels. We therefore conclude that modulation of subthalamic T-type Ca(2+) currents and consequent burst discharges may provide new strategies for the treatment of PD.

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