Matsukawa Hiroshi, Wolf Alexander M, Matsushita Shinichi, Joho Rolf H, Knöpfel Thomas
Laboratory for Neuronal Circuit Dynamics, RIKEN Brain Science Institute, Wako, Japan 351-0198.
J Neurosci. 2003 Aug 20;23(20):7677-84. doi: 10.1523/JNEUROSCI.23-20-07677.2003.
Micelacking both Kv3.1 and both Kv3.3 K+ channel alleles display severe motor deficits such as tremor, myoclonus, and ataxic gait. Micelacking one to three alleles at the Kv3.1 and Kv3.3 loci exhibit in an allele dose-dependent manner a modest degree of ataxia. Cerebellar granule cells coexpress Kv3.1 and Kv3.3 K+ channels and are therefore candidate neurons that might be involved in these behavioral deficits. Hence, we investigated the synaptic mechanisms of transmission in the parallel fiber-Purkinje cell system. Action potentials of parallel fibers were broader in mice lacking both Kv3.1 and both Kv3.3 alleles and in mice lacking both Kv3.1 and a single Kv3.3 allele compared with those of wild-type mice. The transmission of high-frequency trains of action potentials was only impaired at 200 Hz but not at 100 Hz in mice lacking both Kv3.1 and Kv3.3 genes. However, paired-pulse facilitation (PPF) at parallel fiber-Purkinje cell synapses was dramatically reduced in a gene dose-dependent manner in mice lacking Kv3.1 or Kv3.3 alleles. Normal PPF could be restored by reducing the extracellular Ca2+ concentration indicating that increased activity-dependent presynaptic Ca2+ influx, at least in part caused the altered PPF in mutant mice. Induction of metabotropic glutamate receptor-mediated EPSCs was facilitated, whereas longterm depression was not impaired but rather facilitated in Kv3.1/Kv3.3 double-knockout mice. These results demonstrate the importance of Kv3 potassium channels in regulating the dynamics of synaptic transmission at the parallel fiber-Purkinje cell synapse and suggest a correlation between short-term plasticity at the parallel fiber-Purkinje cell synapse and motor performance.
同时缺乏Kv3.1和Kv3.3两个K⁺通道等位基因的小鼠表现出严重的运动缺陷，如震颤、肌阵挛和共济失调步态。在Kv3.1和Kv3.3位点缺乏1至3个等位基因的小鼠以等位基因剂量依赖的方式表现出适度的共济失调。小脑颗粒细胞共表达Kv3.1和Kv3.3 K⁺通道，因此可能是参与这些行为缺陷的候选神经元。因此，我们研究了平行纤维-浦肯野细胞系统中的突触传递机制。与野生型小鼠相比，同时缺乏Kv3.1和Kv3.3两个等位基因的小鼠以及缺乏Kv3.1和单个Kv3.3等位基因的小鼠中，平行纤维的动作电位更宽。在同时缺乏Kv3.1和Kv3.3基因的小鼠中，高频动作电位序列的传递仅在200 Hz时受损，而在100 Hz时未受损。然而，在缺乏Kv3.1或Kv3.3等位基因的小鼠中，平行纤维-浦肯野细胞突触处的双脉冲易化（PPF）以基因剂量依赖的方式显著降低。通过降低细胞外Ca²⁺浓度可以恢复正常的PPF，这表明活性依赖性突触前Ca²⁺内流增加至少部分导致了突变小鼠中PPF的改变。代谢型谷氨酸受体介导的兴奋性突触后电流（EPSC）的诱导得到促进，而在Kv3.1/Kv3.3双敲除小鼠中，长时程抑制未受损反而得到促进。这些结果证明了Kv3钾通道在调节平行纤维-浦肯野细胞突触处突触传递动力学中的重要性，并表明平行纤维-浦肯野细胞突触处的短期可塑性与运动表现之间存在相关性。
