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

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.