Disruption of the olivo-cerebellar circuit by Purkinje neuron-specific ablation of BK channels
Disruption of the olivo-cerebellar circuit by Purkinje neuron-specific ablation of BK channels
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DOI：
10.1073/pnas.1001745107
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发表时间：
2010-07-06
影响因子：
11.1
通讯作者：
Konnerth, Arthur
中科院分区：
文献类型：
--
作者：
Chen, Xiaowei;Kovalchuk, Yury;Konnerth, Arthur
大电导电压激活钾通道和钙激活钾通道在脑内广泛表达，在神经元兴奋的调节中起着重要作用。先前的研究表明，这些通道的完全缺失会导致运动行为受损，这与小脑功能障碍是一致的。细胞分析表明，尖峰电流的下降。环率至少存在于两种类型的小脑神经元，即浦肯野神经元(PNS)和高尔基细胞(Golgi Cell)。为了确定PNS的相对作用，我们开发了一个细胞选择性小鼠突变体，该突变体缺乏PNS特有的功能BK通道。这些小鼠的行为学分析显示出明显的共济失调症状，表明三叉神经节的BK通道对正常的运动协调具有重要作用。通过结合使用双光子成像和膜片钳记录，我们在体内观察到了一种独特的突触功能障碍，即爬升纤维诱发的复合峰活动严重沉默。通过对三叉神经核进行有针对性的药物操作，结合同步的膜片钳记录，我们获得了直接的证据，表明这种爬行纤维活动的沉默是由于三叉神经核-小脑反馈环的故障，包括三叉神经核与小脑深核(DCN)的抑制性突触联系，然后是DCN传入下橄榄的抑制性投射，下橄榄是攀爬纤维的起源。综上所述，我们的结果证实了三叉神经节的BK通道在小脑运动协调和橄榄-小脑环反馈调节中的重要作用。
The large-conductance voltage- and calcium-activated potassium (BK) channels are ubiquitously expressed in the brain and play an important role in the regulation of neuronal excitation. Previous work has shown that the total deletion of these channels causes an impaired motor behavior, consistent with a cerebellar dysfunction. Cellular analyses showed that a decrease in spike. ring rate occurred in at least two types of cerebellar neurons, namely in Purkinje neurons (PNs) and in Golgi cells. To determine the relative role of PNs, we developed a cell-selective mouse mutant, which lacked functional BK channels exclusively in PNs. The behavioral analysis of these mice revealed clear symptoms of ataxia, indicating that the BK channels of PNs are of major importance for normal motor coordination. By using combined two-photon imaging and patch-clamp recordings in these mutant mice, we observed a unique type of synaptic dysfunction in vivo, namely a severe silencing of the climbing fiber-evoked complex spike activity. By performing targeted pharmacological manipulations combined with simultaneous patch-clamp recordings in PNs, we obtained direct evidence that this silencing of climbing fiber activity is due to a malfunction of the tripartite olivo-cerebellar feedback loop, consisting of the inhibitory synaptic connection of PNs to the deep cerebellar nuclei (DCN), followed by a projection of inhibitory DCN afferents to the inferior olive, the origin of climbing fibers. Taken together, our results establish an essential role of BK channels of PNs for both cerebellar motor coordination and feedback regulation in the olivo-cerebellar loop.