Resting Microglia Directly Monitor the Functional State of Synapses In Vivo and Determine the Fate of Ischemic Terminals
Resting Microglia Directly Monitor the Functional State of Synapses In Vivo and Determine the Fate of Ischemic Terminals
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DOI：
10.1523/jneurosci.4363-08.2009
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发表时间：
2009-04-01
影响因子：
5.3
通讯作者：
Nabekura, Junichi
中科院分区：
文献类型：
--
作者：
Wake, Hiroaki;Moorhouse, Andrew J.;Nabekura, Junichi
最近的研究已经确定了神经胶质细胞对神经元回路可塑性的重要贡献。静止的小胶质细胞是大脑中的主要免疫效应细胞，它动态地伸展和收缩自己的过程，就像在积极地观察微环境一样。然而，这些静息的小胶质细胞过程所采集的样本并没有在体内得到证实，小胶质细胞和神经元回路之间任何相互作用的性质和功能也没有完全被理解。利用荧光标记的神经元和小胶质细胞的体内双光子成像，我们证明静息的小胶质细胞过程以大约每小时一次的频率与神经元突触进行短暂（类似于5分钟）和直接接触。这些接触依赖于活动，随着神经元活动的减少而减少。短暂性脑缺血后，这些小胶质细胞-突触接触的持续时间明显延长（类似于1小时），并且经常伴随着突触前钮扣的消失。我们的研究结果表明，至少有一部分静息小胶质过程的动态运动是针对突触的，并提出小胶质细胞警惕地监测和响应突触的功能状态。此外，令人震惊的发现是，在长时间的小胶质细胞接触后，缺血区域的一些突触消失，这表明小胶质细胞有助于随后增加突触连接的周转。进一步了解小胶质细胞检测突触功能状态的机制，以及它们在重塑因缺血而中断的神经元回路中的作用，可能会导致针对小胶质细胞治疗脑损伤的新疗法。
Recent studies have identified the important contribution of glial cells to the plasticity of neuronal circuits. Resting microglia, the primary immune effector cells in the brain, dynamically extend and retract their processes as if actively surveying the microenvironment. However, just what is being sampled by these resting microglial processes has not been demonstrated in vivo, and the nature and function of any interactions between microglia and neuronal circuits is incompletely understood. Using in vivo two-photon imaging of fluorescent-labeled neurons and microglia, we demonstrate that the resting microglial processesmakebrief (similar to 5 min) and direct contacts with neuronal synapses at a frequency of about once per hour. These contacts are activity-dependent, being reduced in frequency by reductions in neuronal activity. After transient cerebral ischemia, the duration of these microglia-synapse contacts are markedly prolonged (similar to 1 h) and are frequently followed by the disappearance of the presynaptic bouton. Our results demonstrate that at least part of the dynamic motility of resting microglial processes in vivo is directed toward synapses and propose that microglia vigilantly monitor and respond to the functional status of synapses. Furthermore, the striking finding that some synapses in the ischemic areas disappear after prolonged microglial contact suggests microglia contribute to the subsequent increased turnover of synaptic connections. Further understanding of the mechanisms involved in the microglial detection of the functional state of synapses, and of their role in remodeling neuronal circuits disrupted by ischemia, may lead to novel therapies for treating brain injury that target microglia.