Aminopyridines Correct Early Dysfunction and Delay Neurodegeneration in a Mouse Model of Spinocerebellar Ataxia Type 1
Aminopyridines Correct Early Dysfunction and Delay Neurodegeneration in a Mouse Model of Spinocerebellar Ataxia Type 1
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DOI：
10.1523/jneurosci.0905-11.2011
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发表时间：
2011-08-17
影响因子：
5.3
通讯作者：
Schiffmann, Serge N.
中科院分区：
文献类型：
--
作者：
Hourez, Raphael;Servais, Laurent;Schiffmann, Serge N.
在脊髓小脑型共济失调1型(SCA1)小鼠模型中，研究了神经元功能障碍对神经变性的贡献，该模型表现为运动能力受损，出现小脑浦肯野细胞的丢失或萎缩。症状前SCA1小鼠表现出浦肯野细胞(无论是在体内还是在切片上)放电率降低，与主要谷氨酸能突触对浦肯野细胞的效率降低和A型钾电流增加有关。A型钾通道Kv4.3似乎内化于浦肯野细胞的谷氨酸能刺激，并在症状前SCA1小鼠体内积聚。用氨基吡啶作为钾通道阻滞剂对SCA1小鼠进行治疗，以测试该治疗是否可以改善神经元功能障碍、运动行为和神经退行性变。在急性治疗的年轻SCA1小鼠中，氨基吡啶使浦肯野细胞的放电率和动物的运动行为正常化。在长期治疗的老年SCA1小鼠中，3，4-二氨基吡啶改善了浦肯野细胞的放电率，改善了动物的运动行为，并部分保护了细胞的萎缩。3，4-二氨基吡啶的慢性治疗与小脑BDNF水平的升高有关，这表明对Purkinje细胞萎缩的部分保护可能是通过增加继发于电活动重新增加的生长因子的产生来提供的。我们的数据表明，氨基吡啶可能对SCA1有症状和/或神经保护作用，浦肯野细胞放电率的降低可以导致小脑性共济失调，早期神经元功能障碍的治疗与SCA1等神经退行性疾病有关。
The contribution of neuronal dysfunction to neurodegeneration is studied in a mouse model of spinocerebellar ataxia type 1 (SCA1) displaying impaired motor performance ahead of loss or atrophy of cerebellar Purkinje cells. Presymptomatic SCA1 mice show a reduction in the firing rate of Purkinje cells (both in vivo and in slices) associated with a reduction in the efficiency of the main glutamatergic synapse onto Purkinje cells and with increased A-type potassium current. The A-type potassium channel Kv4.3 appears to be internalized in response to glutamatergic stimulation in Purkinje cells and accumulates in presymptomatic SCA1 mice. SCA1 mice are treated with aminopyridines, acting as potassium channel blockers to test whether the treatment could improve neuronal dysfunction, motor behavior, and neurodegeneration. In acutely treated young SCA1 mice, aminopyridines normalize the firing rate of Purkinje cells and the motor behavior of the animals. In chronically treated old SCA1 mice, 3,4-diaminopyridine improves the firing rate of Purkinje cells, the motor behavior of the animals, and partially protects against cell atrophy. Chronic treatment with 3,4-diaminopyridine is associated with increased cerebellar levels of BDNF, suggesting that partial protection against atrophy of Purkinje cells is possibly provided by an increased production of growth factors secondary to the reincrease in electrical activity. Our data suggest that aminopyridines might have symptomatic and/or neuroprotective beneficial effects in SCA1, that reduction in the firing rate of Purkinje cells can cause cerebellar ataxia, and that treatment of early neuronal dysfunction is relevant in neurodegenerative disorders such as SCA1.