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 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.

Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys

“…Not surprisingly, local ML218 injections reduced the burst surprise values, the incidence of LTS-like bursts, and the proportion of spikes in rebound and LTS-like bursts. These results confirm previous findings about the effects of this drug on bursting activity in the rat STN (Tai et al 2011;Xiang et al 2011). As expected, ML218 did not strongly affect non-rebound bursting, suggesting that mechanisms other than T-type calcium channel activation may drive non-rebound bursting.…”

Subthalamic discharges as a causal determinant of parkinsonian motor deficits

“…Also, microinjection of T-type Ca 2þ channel blockers directly into STN readily remedies locomotor deficits in a rat model of PD. 28 These findings may suggest a novel mechanistic basis for the therapeutic effect of DBS on PD. DBS settings for the treatment of PD so far have been largely empirical, 29 and are limited to a fairly small range preset by the design of the commercially available implantable pulse generators.…”

“…28 Before electrophysiological record- . Sections were preincubated with 3% normal horse serum in Tris-buffered saline containing 0.3% TritonX-100 (TBST) for 30 minutes at room temperature, and then incubated in TBST containing 1% normal horse serum and monoclonal antibody to tyrosine hydroxylase for 24 hours at 48C.…”

Pacemaker Neurons and Neuronal Networks in Health and Disease

“…Also noteworthy is that highfrequency stimulation of the subthalamic nucleus, which reduces subthalamic busrstiness [62,64], produces a reduction in motor impairments associated with parkinsonism and is currently used in the treatment of parkinsonian patients [63,65]. Moreover, modulation of the T-type calcium channel in subthalamic busrters also reduces parkinsonisms [66].…”