Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcay(ji-hes) mice.
Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcay(ji-hes) mice.
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DOI：
10.1016/j.nbd.2014.03.020
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发表时间：
2014-07
影响因子：
6.1
通讯作者：
Shakkottai VG
中科院分区：
文献类型：
--
作者：
Luna-Cancalon K;Sikora KM;Pappas SS;Singh V;Wulff H;Paulson HL;Burmeister M;Shakkottai VG
最近的证据表明，肌张力障碍，一种以持续的不自主肌肉收缩为特征的运动障碍，可能与小脑异常有关。小脑的功能变化如何导致肌张力障碍的基础知之甚少。在这里，我们确定了Atcayji-hes小鼠的生理学改变，除了共济失调外，还有后肢伸展和脚趾行走的异常步态，让人想起人类肌张力障碍步态。在大脑中没有形态学异常伴随肌张力障碍，但部分小脑切除导致解决僵硬的腿步态，表明小脑功能障碍有助于Atcayji-hes小鼠的肌张力障碍步态。记录急性脑切片中的浦肯野和小脑深核（DCN）神经元，以确定Atcayji-hes小鼠肌张力障碍的生理相关性。大约50%的小脑浦肯野神经元不能显示这些细胞的正常重复放电特征。此外，DCN神经元表现出增加的固有放电频率，其中一部分神经元表现出动作电位的爆发。DCN神经元的这种增加的内在兴奋性伴随着由小电导钙激活钾（SK）通道介导的后超极化电流的减少。SK通道激活剂降低急性小脑切片中DCN神经元放电频率并改善Atcayji-hes小鼠的张力障碍步态。这些结果表明，浦肯野神经元活性降低和DCN内在兴奋性增加的组合可导致小鼠共济失调和肌张力障碍样步态的组合。
Recent evidence suggests that dystonia, a movement disorder characterized by sustained involuntary muscle contractions, can be associated with cerebellar abnormalities. The basis for how functional changes in the cerebellum can cause dystonia is poorly understood. Here we identify alterations in physiology in Atcayji-hes mice which in addition to ataxia, have an abnormal gait with hind limb extension and toe walking, reminiscent of human dystonic gait. No morphological abnormalities in the brain accompany the dystonia, but partial cerebellectomy causes resolution of the stiff-legged gait, suggesting that cerebellar dysfunction contributes to the dystonic gait of Atcayji-hes mice. Recordings from Purkinje and deep cerebellar nuclear (DCN) neurons in acute brain slices were used to determine the physiological correlates of dystonia in the Atcayji-hes mice. Approximately 50% of cerebellar Purkinje neurons fail to display the normal repetitive firing characteristic of these cells. In addition, DCN neurons exhibit increased intrinsic firing frequencies with a subset of neurons displaying bursts of action potentials. This increased intrinsic excitability of DCN neurons is accompanied by a reduction in after-hyperpolarization currents mediated by small-conductance calcium-activated potassium (SK) channels. An activator of SK channels reduces DCN neuron firing frequency in acute cerebellar slices and improves the dystonic gait of Atcayji-hes mice. These results suggest that a combination of reduced Purkinje neuron activity and increased DCN intrinsic excitability can result in a combination of ataxia and a dystonia-like gait in mice.
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影响因子：
3.7
作者：
Buschdorf JP;Chew LL;Soh UJ;Liou YC;Low BC
通讯作者：
Low BC
影响因子：
2.5
作者：
Aizenman, CD;Linden, DJ
通讯作者：
Linden, DJ
影响因子：
4
作者：
Buschdorf, Jan Paul;Chew, Li Li;Low, Boon Chuan
通讯作者：
Low, Boon Chuan
影响因子：
11.2
作者：
Eidelberg, D;Moeller, JR;Fahn, S
通讯作者：
Fahn, S
影响因子：
25
作者：
Hoshi, E;Tremblay, L;Strick, PL
通讯作者：
Strick, PL