Optogenetic Countering of Glial Acidosis Suppresses Glial Glutamate Release and Ischemic Brain Damage
Optogenetic Countering of Glial Acidosis Suppresses Glial Glutamate Release and Ischemic Brain Damage
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DOI：
10.1016/j.neuron.2013.11.011
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发表时间：
2014-01-22
期刊：
影响因子：
16.2
通讯作者：
Matsui, Ko
中科院分区：
文献类型：
--
作者：
Beppu, Kaoru;Sasaki, Takuya;Matsui, Ko
大脑需要高能量供应，血流受阻会导致脑细胞健康状况迅速恶化。缺血时会发生两个主要事件：酸中毒和过量谷氨酸的释放，这会导致兴奋性毒性。然而，谷氨酸的细胞来源及其在缺血时的释放机制尚不清楚。在这里，我们展示了神经胶质酸中毒和神经元兴奋性毒性之间的因果关系。由于流经通道视紫红质-2(ChR2)的主要阳离子是质子，这可以被认为是一种瞬间细胞内酸化的光遗传工具。光激活表达于神经胶质细胞的ChR2导致神经胶质酸化和谷氨酸的释放。另一方面，通过光遗传激活质子泵--古紫红质(ARCHT)使胶质细胞碱化，导致体内谷氨酸释放停止，从而减轻缺血性脑损伤。我们的结果提示，控制胶质细胞的pH值可能是干预缺血性脑损伤的一种有效的治疗策略。
The brain demands high-energy supply and obstruction of blood flow causes rapid deterioration of the healthiness of brain cells. Two major events occur upon ischemia: acidosis and liberation of excess glutamate, which, leads to excitotoxicity. However, cellular source of glutamate and its release mechanism upon ischemia remained unknown. Here we show a causal relationship between glial acidosis and neuronal excitotoxicity. As the major cation that flows through channelrhodopsin-2 (ChR2) is proton, this could be regarded as an optogenetic tool for instant intracellular acidification. Optical activation of ChR2 expressed in glial cells led to glial acidification and to release of glutamate. On the other hand, glial alkalization via optogenetic activation of a proton pump, archaerhodopsin (ArchT), led to cessation of glutamate release and to the relief of ischemic brain damage in vivo. Our results suggest that controlling glial pH may be an effective therapeutic strategy for intervention of ischemic brain damage.