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首页> 外文期刊>Journal of Neurophysiology >In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model
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In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model

机译：SCA2转基因小鼠模型中小脑浦肯野细胞活性的体内分析

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摘要

Cerebellar Purkinje cells (PCs) are primarily affected in many spinocerebellar ataxias (SCA). In this study we investigated functional activity of PCs in transgenic mouse model of SCA2, a polyglutamine neurodegenerative hereditary disorder. In our studies we used extracellular single-unit recording method to compare spontaneous activity of PCs in age-matched wild-type mice and SCA2-58Q transgenic mice. We discovered that the fraction of PCs with bursting and an irregular pattern of spontaneous activity dramatically increases in aged SCA2-58Q mice compared with wild-type littermates. Small-conductance calcium-activated potassium (SK) channels play an important role in determining firing rate of PCs. Indeed, we demonstrated that intraperitoneal (IP) injection of SK channel inhibitor NS8593 induces an irregular pattern of PC activity in wild-type mice. Furthermore, we demonstrated that IP injection of SK channel-positive modulator chlorzoxazone (CHZ) decreases spontaneous firing rate of cerebellar PCs. Finally, we have shown that IP injections with CHZ normalize firing activity of cerebellar PCs from aging SCA2-58Q mice. We propose that alterations in PC firing patterns is one of potential causes of ataxic symptoms in SCA2 and in other SCAs and that positive modulators of SK channels can be used to normalize activity of PCs and alleviate ataxic phenotype in patients with SCA.
机译：小脑浦肯野细胞（PCs）主要受许多脊髓小脑共济失调（SCA）的影响。在这项研究中，我们调查了PCs在SCA2（一种多聚谷氨酰胺神经变性遗传性疾病）的转基因小鼠模型中的功能活性。在我们的研究中，我们使用细胞外单单位记录方法来比较年龄匹配的野生型小鼠和SCA2-58Q转基因小鼠中PC的自发活性。我们发现，与野生型同窝仔相比，年龄较大的SCA2-58Q小鼠中具有破裂和自发活动的不规则模式的PC分数显着增加。小电导钙激活钾（SK）通道在确定PC的发射速率中起重要作用。实际上，我们证明了腹膜内（IP）注射SK通道抑制剂NS8593在野生型小鼠中诱导PC活动的不规则模式。此外，我们证明IP注射SK通道阳性调节剂氯唑沙宗（CHZ）会降低小脑PC的自发放电率。最后，我们已经证明，用CHZ进行IP注射可使来自衰老的SCA2-58Q小鼠的小脑PC的放电活性正常化。我们提出，PC放电模式的改变是SCA2和其他SCA中共济失调症状的潜在原因之一，并且SK通道的正调节剂可用于使SCA患者的PC活性正常化并减轻其共济失调表型。

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