Microglial Contact Prevents Excess Depolarization and Rescues Neurons from Excitotoxicity.
Microglial Contact Prevents Excess Depolarization and Rescues Neurons from Excitotoxicity.
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小胶质细胞接触可防止过度的去极化，并挽救神经元的兴奋性毒性。
DOI：
10.1523/eneuro.0004-16.2016
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发表时间：
2016-05
期刊：
影响因子：
3.4
通讯作者：
Nabekura J
中科院分区：
文献类型：
--
作者：
Kato G;Inada H;Wake H;Akiyoshi R;Miyamoto A;Eto K;Ishikawa T;Moorhouse AJ;Strassman AM;Nabekura J
小胶质细胞调查并直接接触健康和受损大脑中的神经元，但这些接触的机制和功能后果尚未完全阐明。结合双光子成像和膜片箝位技术，我们建立了一个急性实验模型，用于研究小胶质细胞在神经元过度活跃引起的中枢神经系统兴奋性毒性中的作用。我们的模型允许我们使用Iba-1 eGFP小鼠的皮质脑切片，同时检查重复的最大刺激对轴突形态、神经元膜电位和小胶质细胞迁移的影响。我们证明小胶质细胞在神经元过度活跃的情况下发挥急性和高度局部的神经保护作用。唤醒单个2/3层锥体神经元的重复动作电位会引起轴突肿胀，但不会引起树突肿胀，这伴随着大量持续的体膜电位去极化。小胶质细胞迁移到这些肿胀的轴突的机制包括ATP和谷氨酸通过体积激活的阴离子通道释放。这种迁移之后，受影响的轴突被密集的小胶质包裹，在某些情况下，轴突碎片的去除会导致快速的体细胞膜复极化回到静息电位。当小胶质细胞的迁移被药物阻断时，活动诱导的去极化持续到细胞死亡，这表明小胶质细胞与轴突的接触有助于防止体细胞的病理性去极化并维持神经元的活力。这是小胶质细胞监测的一个新方面：检测、包裹和拯救由于过度活动造成的神经元体细胞损伤。
Microglia survey and directly contact neurons in both healthy and damaged brain, but the mechanisms and functional consequences of these contacts are not yet fully elucidated. Combining two-photon imaging and patch clamping, we have developed an acute experimental model for studying the role of microglia in CNS excitotoxicity induced by neuronal hyperactivity. Our model allows us to simultaneously examine the effects of repetitive supramaximal stimulation on axonal morphology, neuronal membrane potential, and microglial migration, using cortical brain slices from Iba-1 eGFP mice. We demonstrate that microglia exert an acute and highly localized neuroprotective action under conditions of neuronal hyperactivity. Evoking repetitive action potentials in individual layer 2/3 pyramidal neurons elicited swelling of axons, but not dendrites, which was accompanied by a large, sustained depolarization of soma membrane potential. Microglial processes migrated to these swollen axons in a mechanism involving both ATP and glutamate release via volume-activated anion channels. This migration was followed by intensive microglial wrapping of affected axons and, in some cases, the removal of axonal debris that induced a rapid soma membrane repolarization back to resting potentials. When the microglial migration was pharmacologically blocked, the activity-induced depolarization continued until cell death ensued, demonstrating that the microglia–axon contact served to prevent pathological depolarization of the soma and maintain neuronal viability. This is a novel aspect of microglia surveillance: detecting, wrapping, and rescuing neuronal soma from damage due to excessive activity.