Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia.
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Sci Rep. 2023 Aug 3;13(1):12588. doi: 10.1038/s41598-023-39331-y.
Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder caused by a pathological expansion of CAG repeats in ATXN2 gene. SCA2 is accompanied by cerebellar degeneration and progressive motor decline. Cerebellar Purkinje cells (PCs) seem to be primarily affected in this disorder. The majority of the ataxia research is focused on the motor decline observed in ataxic patients and animal models of the disease. However, recent evidence from patients and ataxic mice suggests that SCA2 can also share the symptoms of the cerebellar cognitive affective syndrome. We previously reported that SCA2-58Q PC-specific transgenic mice exhibit anxiolytic behavior, decline in spatial memory, and a depressive-like state. Here we studied the effect of the activation of the small conductance calcium-activated potassium channels (SK channels) by chlorzoxazone (CHZ) combined with the folic acid (FA) on the PC firing and also motor, cognitive and affective symptoms in SCA2-58Q mice. We realized that CHZ-FA combination improved motor and cognitive decline as well as ameliorated mood alterations in SCA2-58Q mice without affecting the firing rate of their cerebellar PCs. Our results support the idea of the combination therapy for both ataxia and non-motor symptoms in ataxic mice without affecting the firing frequency of PCs.
脊髓小脑共济失调 2 型(SCA2)是一种多聚谷氨酰胺疾病,由 ATXN2 基因中 CAG 重复序列的病理性扩张引起。SCA2 伴有小脑变性和进行性运动下降。小脑浦肯野细胞(PCs)似乎是该疾病的主要受影响细胞。大多数共济失调研究都集中在共济失调患者和疾病动物模型中观察到的运动下降上。然而,最近来自患者和共济失调小鼠的证据表明,SCA2 也可能具有小脑认知情感综合征的症状。我们之前报道过 SCA2-58Q PC 特异性转基因小鼠表现出焦虑样行为、空间记忆下降和抑郁样状态。在这里,我们研究了氯唑沙宗(CHZ)联合叶酸(FA)激活小电导钙激活钾通道(SK 通道)对 SCA2-58Q 小鼠 PC 放电以及运动、认知和情感症状的影响。我们意识到 CHZ-FA 联合治疗改善了 SCA2-58Q 小鼠的运动和认知衰退以及情绪改变,而不影响其小脑 PCs 的放电率。我们的结果支持在不影响 PCs 放电频率的情况下,对共济失调小鼠进行联合治疗以治疗共济失调和非运动症状的想法。
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