Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, China.
National Clinical Research Center for Child Health and Disorders, Chongqing, China.
CNS Neurosci Ther. 2024 Feb;30(2):e14352. doi: 10.1111/cns.14352. Epub 2023 Jul 12.
This study aimed to investigate whether minocycline could influence alterations of microglial subtypes, the morphology of dendrites and dendritic spines, the microstructures of synapses and synaptic proteins, or even cognition outcomes in immature male mice following status epilepticus (SE) induced by kainic acid.
Golgi staining was performed to visualize the dendrites and dendritic spines of neurons of the hippocampus. The microstructures of synapses and synaptic proteins were observed using transmission electron microscopy and western blotting analysis, respectively. Microglial reactivation and their markers were evaluated using flow cytometry. The Morris water maze (MWM) test was used to analyze spatial learning and memory ability.
Significant partial spines increase (predominate in thin spines) was observed in the dendrites of neurons after acute SE and partial loss (mainly in thin spines) was presented by days 14 and 28 post-SE. The postsynaptic ultrastructure was impaired on the 7th and 14th days after SE. The proportion of M1 microglia increased significantly only after acute SE Similarly, the proportion of M2 microglia increased in the acute stage with high expression levels of all surface markers. In contrast, a decrease in M2 microglia and their markers was noted by day 14 post-SE. Minocycline could reverse the changes in dendrites and synaptic proteins caused by SE, and increase the levels of synaptic proteins. Meanwhile, minocycline could inhibit the reactivation of M1 microglia and the expression of their markers, except for promoting CD200R. In addition, treatment with minocycline could regulate the expression of M2 microglia and their surface markers, as well as ameliorating the impaired spatial learning and memory on the 28th day after SE.
Dendritic spines and microglia are dynamically changed after SE. Minocycline could ameliorate the impaired cognition in the kainic acid-induced mouse model by decreasing the damage to dendrites and altering microglial reactivation.
本研究旨在探讨米诺环素是否能影响癫痫持续状态（SE）后未成熟雄性小鼠小胶质细胞亚型的改变、树突和树突棘的形态、突触和突触蛋白的微结构，甚至认知结果。
通过高尔基染色观察海马神经元树突和树突棘的形态。通过透射电子显微镜和western blot 分析观察突触和突触蛋白的微结构。通过流式细胞术评估小胶质细胞的再激活及其标志物。采用 Morris 水迷宫（MWM）试验分析空间学习和记忆能力。
急性 SE 后神经元树突中可见明显的部分棘突增加（以细棘突为主），SE 后 14 天和 28 天可见部分棘突丢失（主要以细棘突为主）。SE 后第 7 天和第 14 天突触后超微结构受损。急性 SE 后仅 M1 小胶质细胞的比例显著增加。同样，急性阶段 M2 小胶质细胞的比例增加，所有表面标志物的表达水平升高。相反，SE 后 14 天 M2 小胶质细胞及其标志物的数量减少。米诺环素可逆转 SE 引起的树突和突触蛋白变化，并增加突触蛋白水平。同时，米诺环素可抑制 M1 小胶质细胞的再激活及其标志物的表达，除了促进 CD200R 表达。此外，米诺环素治疗可调节 M2 小胶质细胞及其表面标志物的表达，改善 SE 后第 28 天受损的空间学习和记忆。
SE 后树突棘和小胶质细胞发生动态变化。米诺环素通过减少树突损伤和改变小胶质细胞再激活，改善 SE 后认知障碍。
