Graduate Biomedical Sciences Neuroscience Theme, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, AL, USA.
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, AL, USA.
Exp Neurol. 2020 Aug;330:113358. doi: 10.1016/j.expneurol.2020.113358. Epub 2020 May 7.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine expansion in the widely expressed huntingtin protein. Multiple studies have indicated the importance of mutant huntingtin (mHTT) in astrocytes to HD pathogenesis. Astrocytes exhibit SNARE-dependent exocytosis and gliotransmission, which can be hampered by transgenic expression of dominant negative SNARE (dnSNARE) in these glial cells. We used BACHD mice and crossed them with the dnSNARE model to determine if pan-astrocytic SNARE-dependent exocytosis plays an important role in vivo in the progression of HD behavioral phenotypes. We assessed motor and neuropsychiatric behaviors in these mice. At 12 months of age there was a significant improvement in motor coordination (rotarod test) in BACHD/dnSNARE mice when compared to BACHD mice. Analyses of open field performance revealed significant worsening of center entry (at 9 and 12 months), but not distance traveled in BACHD/dnSNARE when compared to BACHD mice, and variable/inconclusive results on vertical plane entry. While no differences between BACHD and BACHD/dnSNARE mice at 12 months of age in the forced swim test were found, we did observe a significant decrease in performance of BACHD/dnSNARE mice in the light-dark box paradigm. Thus, reduction of astrocytic SNARE-dependent exocytosis has differential effects on the psychiatric-like and motor phenotypes observed in BACHD mice. These data suggest broadly targeting SNARE-dependent exocytosis in astrocytes throughout the brain as a means to modulate gliotransmission in HD may contribute to worsening of specific behavioral deficits and perhaps a brain-region specific approach would be required.
亨廷顿病（HD）是一种由广泛表达的亨廷顿蛋白中的多聚谷氨酰胺扩展引起的显性遗传性神经退行性疾病。多项研究表明，突变型亨廷顿蛋白（mHTT）在星形胶质细胞中对 HD 发病机制很重要。星形胶质细胞表现出 SNARE 依赖性胞吐作用和神经胶质传递，而这些胶质细胞中转基因表达显性负性 SNARE（dnSNARE）会阻碍其发生。我们使用 BACHD 小鼠并将其与 dnSNARE 模型进行杂交，以确定星形胶质细胞中 SNARE 依赖性胞吐作用是否在体内对 HD 行为表型的进展起重要作用。我们评估了这些小鼠的运动和神经精神行为。在 12 个月大时，与 BACHD 小鼠相比，BACHD/dnSNARE 小鼠的运动协调能力（转棒测试）有显著改善。对旷场表现的分析显示，在 BACHD/dnSNARE 小鼠中，中心进入（在 9 个月和 12 个月时）显著恶化，但与 BACHD 小鼠相比，行进距离没有变化，而在垂直平面进入方面则得到了可变/不确定的结果。虽然在 12 个月大时，在强迫游泳试验中没有发现 BACHD 和 BACHD/dnSNARE 小鼠之间的差异，但我们确实观察到 BACHD/dnSNARE 小鼠在明暗箱范式中的表现显著下降。因此，减少星形胶质细胞 SNARE 依赖性胞吐作用对 BACHD 小鼠中观察到的精神病样和运动表型有不同的影响。这些数据表明，广泛靶向星形胶质细胞中的 SNARE 依赖性胞吐作用作为调节 HD 中神经胶质传递的一种手段，可能会导致特定行为缺陷的恶化，也许需要一种特定脑区的方法。
