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 3

Spontaneous firing activities of subthalamic neurons in acute brain slices.

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Spontaneous firing activities of subthalamic neurons in acute brain slic...
(A) Examples of cell-attached patch-clamp recordings of spontaneous subthalamic discharges in acute brain slices of normal mice and of parkinsonian rats (each sweep represents a 30-second recording). Subthalamic neurons in normal mice may exhibit spiking (tonic), burst (phasic), or mixed patterns of firing, whereas the neurons in parkinsonian rats tend to be either silent or firing in bursts with longer intra-burst duration. The corresponding histogram plot for each of the sample traces is presented on the right end of each trace. The histogram plot shows a clear peak in the inverse of the inter-spike interval (ISI) for the spiking (tonic) firing, representing regular spikes at a frequency of approximately 10 Hz. In contrast, there is a smear in the higher frequencies plus a single peak at an extremely low frequency for the burst firing mode, consistent with periodic occurrence of irregular but high-frequency bursts of discharges. Scale bar: 2 seconds. (B–E) Comparison of different parameters of STN firing recorded from acute slices (in vitro, n = 6) with those from in vivo single-unit recording data (taken from Figures 7 and 8). P = 0.24, 0.53, 0.31, and 0.41 for B, C, D, and E, respectively.