Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203.
Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203
J Neurosci. 2020 Apr 22;40(17):3332-3347. doi: 10.1523/JNEUROSCI.1644-19.2020. Epub 2020 Mar 13.
To determine whether Cav1.2 voltage-gated Ca channels contribute to astrocyte activation, we generated an inducible conditional knock-out mouse in which the Cav1.2 α subunit was deleted in GFAP-positive astrocytes. This astrocytic Cav1.2 knock-out mouse was tested in the cuprizone model of myelin injury and repair which causes astrocyte and microglia activation in the absence of a lymphocytic response. Deletion of Cav1.2 channels in GFAP-positive astrocytes during cuprizone-induced demyelination leads to a significant reduction in the degree of astrocyte and microglia activation and proliferation in mice of either sex. Concomitantly, the production of proinflammatory factors such as TNFα, IL1β and TGFβ1 was significantly decreased in the corpus callosum and cortex of Cav1.2 knock-out mice through demyelination. Furthermore, this mild inflammatory environment promotes oligodendrocyte progenitor cells maturation and myelin regeneration across the remyelination phase of the cuprizone model. Similar results were found in animals treated with nimodipine, a Cav1.2 Ca channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the cuprizone treatment displayed a reduced number of reactive astrocytes and showed a faster and more efficient brain remyelination. Together, these results indicate that Cav1.2 Ca channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and that attenuation of astrocytic voltage-gated Ca influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases. Reducing voltage-gated Ca influx in astrocytes during brain demyelination significantly attenuates brain inflammation and astrocyte reactivity. Furthermore, these changes promote myelin restoration and oligodendrocyte maturation throughout remyelination.
为了确定 Cav1.2 电压门控钙通道是否有助于星形胶质细胞的激活，我们生成了一种可诱导的条件性敲除小鼠，其中 Cav1.2α亚基在 GFAP 阳性星形胶质细胞中被删除。在脱髓鞘模型中测试了这种星形胶质细胞 Cav1.2 敲除小鼠，该模型在没有淋巴细胞反应的情况下导致星形胶质细胞和小胶质细胞的激活。在杯状朊病毒诱导的脱髓鞘期间，GFAP 阳性星形胶质细胞中 Cav1.2 通道的缺失导致两性小鼠中星形胶质细胞和小胶质细胞的激活和增殖程度显著降低。同时，通过脱髓鞘，Cav1.2 敲除小鼠胼胝体和皮质中 TNFα、IL1β 和 TGFβ1 等促炎因子的产生显著减少。此外，这种轻度炎症环境促进少突胶质细胞前体细胞在脱髓鞘模型的再髓鞘化阶段成熟和髓鞘再生。在接受尼莫地平治疗的动物中也发现了类似的结果，尼莫地平是一种对中枢神经系统具有高亲和力的 Cav1.2 Ca 通道抑制剂。在杯状朊病毒治疗的脱髓鞘阶段给两性小鼠注射尼莫地平，显示出较少的反应性星形胶质细胞，并且显示出更快和更有效的大脑再髓鞘化。总之，这些结果表明 Cav1.2 Ca 通道在脱髓鞘过程中星形胶质细胞的诱导和增殖中起关键作用；并且减弱星形胶质细胞电压门控 Ca 内流可能是减少脑炎症和促进脱髓鞘疾病中髓鞘恢复的有效治疗方法。在脑脱髓鞘期间减少星形胶质细胞中的电压门控 Ca 内流可显著减轻脑炎症和星形胶质细胞反应性。此外，这些变化促进了整个再髓鞘化过程中的髓鞘修复和少突胶质细胞成熟。
