Dell'Orco James M, Pulst Stefan M, Shakkottai Vikram G
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48103, USA.
Department of Neurology, University of Utah, Salt Lake City, UT 84112, USA.
Hum Mol Genet. 2017 Oct 15;26(20):3935-3945. doi: 10.1093/hmg/ddx281.
Alterations in Purkinje neuron firing often accompany ataxia, but the molecular basis for these changes is poorly understood. In a mouse model of spinocerebellar ataxia type 2 (SCA2), a progressive reduction in Purkinje neuron firing frequency accompanies cell atrophy. We investigated the basis for altered Purkinje neuron firing in SCA2. A reduction in the expression of large-conductance calcium-activated potassium (BK) channels and Kv3.3 voltage-gated potassium channels accompanies the inability of Purkinje neurons early in disease to maintain repetitive spiking. In association with prominent Purkinje neuron atrophy, repetitive spiking is restored, although at a greatly reduced firing frequency. In spite of a continued impairment in spike repolarization and a persistently reduced BK channel mediated afterhyperpolarization (AHP), repetitive spiking is maintained, through the increased activity of barium-sensitive potassium channels, most consistent with inwardly rectifying potassium (Kir) channels. Increased activity of Kir channels results in the generation of a novel AHP not seen in wild-type Purkinje neurons that also accounts for the reduced firing frequency late in disease. Homeostatic changes in Purkinje neuron morphology that help to preserve repetitive spiking can also therefore have deleterious consequences for spike frequency. These results suggest that the basis for spiking abnormalities in SCA2 differ depending on disease stage, and interventions targeted towards correcting potassium channel dysfunction in ataxia need to be tailored to the specific stage in the degenerative process.
浦肯野神经元放电的改变常伴随共济失调，但这些变化的分子基础却知之甚少。在2型脊髓小脑共济失调（SCA2）的小鼠模型中，浦肯野神经元放电频率的逐渐降低伴随着细胞萎缩。我们研究了SCA2中浦肯野神经元放电改变的基础。在疾病早期，浦肯野神经元无法维持重复放电，同时大电导钙激活钾（BK）通道和Kv3.3电压门控钾通道的表达减少。尽管尖峰复极化持续受损且BK通道介导的超极化后电位（AHP）持续降低，但随着浦肯野神经元显著萎缩，重复放电得以恢复，不过放电频率大幅降低。通过钡敏感钾通道（最符合内向整流钾通道（Kir））活性的增加，尽管存在持续的尖峰复极化损伤和BK通道介导的AHP持续降低，重复放电仍得以维持。Kir通道活性增加导致产生了野生型浦肯野神经元中未见的新型AHP，这也解释了疾病后期放电频率降低的原因。因此，有助于维持重复放电的浦肯野神经元形态的稳态变化也可能对放电频率产生有害影响。这些结果表明，SCA2中放电异常的基础因疾病阶段而异，针对共济失调中钾通道功能障碍进行纠正的干预措施需要根据退化过程中的特定阶段进行调整。
