Purkinje-cell-restricted restoration of Kv3.3 function restores complex spikes and rescues motor coordination in Kcnc3 mutants
Purkinje-cell-restricted restoration of Kv3.3 function restores complex spikes and rescues motor coordination in Kcnc3 mutants
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DOI：
10.1523/jneurosci.5486-07.2008
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发表时间：
2008-04-30
影响因子：
5.3
通讯作者：
Joho, Rolf H.
中科院分区：
文献类型：
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作者：
Hurlock, Edward C.;McMahon, Anne;Joho, Rolf H.
快速激活/失活电压门控钾通道 Kv3.3 (Kcnc3) 在参与运动功能的各种神经元细胞类型中表达，包括小脑浦肯野细胞。携带 Kcnc3 显性失活突变和 Kcnc3 缺失突变小鼠的脊髓小脑共济失调 13 型 (SCA13) 患者均表现出运动不协调，这表明小鼠在窄梁上行走和滑倒时横向偏差增加。然而，运动技能学习却幸免于难。缺乏 Kcnc3 的小鼠也会表现出肌肉抽搐。除了加宽的尖峰之外，Kcnc3 缺失浦肯野细胞的记录还显示，复杂尖峰中的小穗较少，并且内部爆发频率较低。 Kv3.3 通道仅在 Kcnc3 缺失小鼠以及 Kv3.1 杂合小鼠的浦肯野细胞中进行靶向重新表达，足以恢复简单尖峰的简洁性以及正常的复杂尖峰，并挽救特异性协调。因此，浦肯野细胞中需要 Kv3.3 功能的尖峰参数涉及共济失调无效表型和运动协调，但不涉及运动学习。
The fast-activating/deactivating voltage-gated potassium channel Kv3.3 (Kcnc3) is expressed in various neuronal cell types involved in motor function, including cerebellar Purkinje cells. Spinocerebellar ataxia type 13 (SCA13) patients carrying dominant-negative mutations in Kcnc3 and Kcnc3-null mutant mice both display motor incoordination, suggested in mice by increased lateral deviation while ambulating and slips on a narrow beam. Motor skill learning, however, is spared. Mice lacking Kcnc3 also exhibit muscle twitches. In addition to broadened spikes, recordings of Kcnc3-null Purkinje cells revealed fewer spikelets in complex spikes and a lower intraburst frequency. Targeted reexpression of Kv3.3 channels exclusively in Purkinje cells in Kcnc3-null mice as well as in mice also heterozygous for Kv3.1 sufficed to restore simple spike brevity along with normal complex spikes and to rescue specifically coordination. Therefore, spike parameters requiring Kv3.3 function in Purkinje cells are involved in the ataxic null phenotype and motor coordination, but not motor learning.