In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model
In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model
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DOI：
10.1152/jn.00913.2015
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发表时间：
2016-06-01
影响因子：
2.5
通讯作者：
Bezprozvanny, Ilya B.
中科院分区：
文献类型：
--
作者：
Egorova, Polina A.;Zakharova, Olga A.;Bezprozvanny, Ilya B.
小脑浦肯野细胞（PC）主要在许多脊髓小脑共济失调（SCA）中受到影响。在这项研究中，我们研究了功能活动的PC在转基因小鼠模型SCA 2，多聚谷氨酰胺神经退行性遗传性疾病。本研究采用细胞外单细胞记录法比较了年龄匹配的野生型小鼠和SCA 2 - 58 Q转基因小鼠的PC自发活动。我们发现，与野生型同窝小鼠相比，老年SCA 2 - 58 Q小鼠中具有爆发和不规则自发活动模式的PC的分数显著增加。小电导钙激活钾（SK）通道在决定PC放电频率中起重要作用。事实上，我们证明，腹膜内（IP）注射SK通道抑制剂NS 8593诱导野生型小鼠PC活性的不规则模式。此外，我们证明了IP注射SK通道阳性调节剂氯唑沙宗（CHZ）降低小脑PC的自发放电率。最后，我们已经表明，IP注射CHZ使来自老化SCA 2 - 58 Q小鼠的小脑PC的放电活动正常化。我们认为PC放电模式的改变是SCA 2和其他SCA中共济失调症状的潜在原因之一，SK通道的正调节剂可用于使PC的活性正常化并减轻SCA患者的共济失调表型。
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.