Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment
Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment
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DOI：
10.1016/j.neuron.2019.04.032
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发表时间：
2019-07-17
期刊：
影响因子：
16.2
通讯作者：
Monje, Michelle
中科院分区：
文献类型：
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作者：
Geraghty, Anna C.;Gibson, Erin M.;Monje, Michelle
活动依赖性髓鞘形成被认为有助于适应性神经功能。然而，活动调节髓鞘形成的机制以及髓鞘可塑性对非运动认知功能的贡献程度仍然不完全清楚。使用化疗相关的认知障碍（CRCI）的小鼠模型，我们最近证明，甲氨蝶呤（MTX）化疗诱导复杂的神经胶质细胞功能障碍，其中小胶质细胞活化是中央。在这里，我们证明了远程MTX暴露阻断活性调节的髓鞘形成。MTX降低皮质BDNF表达，其通过小胶质细胞耗竭恢复。Bdnf-TrkB信号传导是活性依赖性髓鞘形成的必需组分。化疗初治小鼠中少突胶质细胞前体细胞（OPC）特异性TrkB缺失导致认知行为表现受损。小分子TrkB激动剂在MTX化疗后挽救髓鞘形成和认知障碍MTX后的这种拯救依赖于OPC中完整的TrkB表达。综上所述，这些发现表明了适应性髓鞘形成所需的分子机制，该机制在CRCI中由于小胶质细胞活化而异常。
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.