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首页> 外文期刊>The journal of clinical investigation >Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease
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Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease

机译：丘脑下T型Ca 2+通道的调节可弥补帕金森病大鼠模型中的运动功能障碍

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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.
机译：丘脑下核（STN）中神经元爆发活动的增加是帕金森病（PD）的有据可查的电生理特征。然而，丘脑底下爆发与PD症状之间的因果关系以及爆发背后的离子机制仍有待建立。在这里，我们已经表明，T型Ca〜（2+）通道对于丘脑底下爆发射击是必需的，并且在PD大鼠模型中，T型Ca〜（2+）通道的药理阻断作用可降低运动功能障碍。 Ni〜（2+），米贝拉地尔，NNC 55-0396和依非地平抑制急性离解的STN神经元中的T型Ca〜（2+）电流，但Cd〜（2+）和硝苯地平则无此作用，后者优先抑制L型或其他非T型Ca〜（2+）电流有效地减少了STN切片中的爆发活动。局部给予T型Ca〜（2+）通道抑制剂可降低PD大鼠模型的体内STN爆发活性并显着减少运动功能障碍。 Cd〜（2+）和硝苯地平没有这种电生理和行为效应。虽然低频深部脑刺激（DBS）被认为对PD无效，但我们发现延长低频去极化脉冲的持续时间有效地改善了PD大鼠模型的运动行为指标，大概是通过降低T的可用性型Ca〜（2+）通道。因此，我们得出的结论是，丘脑下T型Ca〜（2+）电流的调制和随之而来的突发放电可能为PD的治疗提供新的策略。

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