Functional changes of glutamate transporters during ischemia.

谷氨酸转运体将谷氨酸从细胞外空间移除，并在正常情况下将其维持在神经毒性水平以下。然而，缺血条件下的动态仍有待确定。在本研究中，我们通过体内脑微透析技术评估了突变小鼠脑缺血时胶质谷氨酸转运体（GLT-1）和神经元谷氨酸转运体（EAAC1）的功能。在突变型和野生型小鼠的海马CA1中放置微透析探针，在缺血5分钟和20分钟时测量谷氨酸水平。GLT-1缺失小鼠在缺血5 min时谷氨酸水平明显高于野生型小鼠。GLT-1缺失小鼠的CA1可诱导延迟性神经元死亡，而野生型小鼠的CA1无延迟性神经元死亡。当缺血时间延长至20 min时，在缺血20 min的最后12.5 min，野生型小鼠的谷氨酸水平显著高于GLT-1缺失小鼠。在野生型小鼠CA1中也观察到急性神经元死亡。这些结果表明，GLT-1在缺血早期吸收细胞外谷氨酸保护神经元，然后在缺血状态延长时释放谷氨酸，引发急性神经元死亡。缺血时GLT-1的功能可能由神经保护向神经退行性转变。缺乏EAAC1的小鼠在缺血时谷氨酸水平明显低于野生型小鼠。这表明EAAC1在缺血后立即释放谷氨酸。EAAC1可能在缺血早期起神经退行性作用。

Glutamate transporters remove glutamate from the extracellular space and maintain it below neurotoxic levels under normal conditions. However, the dynamics under ischemic conditions remain to be determined. In the present study, we evaluated the function of the glial glutamate transporter (GLT-1) and neuronal glutamate transporter (EAAC1) during brain ischemia, by using an in vivo brain microdialysis technique in the mutant mice. A microdialysis probe was placed in the hippocampal CA1 of the mutant and wild-type mice, and glutamate levels were measured during 5- and 20-min ischemia. The glutamate levels in mice lacking GLT-1 were significantly higher than the corresponding glutamate levels in wild-type mice during 5-min ischemia. Delayed neuronal death was induced in the CA1 of the mice lacking GLT-1 but not in the CA1 of the wild-type mice. When ischemia was elongated to the duration of 20 min, the glutamate levels in wild-type mice were significantly higher than the corresponding glutamate levels in mice lacking GLT-1 during the last 12.5 min of 20-min ischemia. Acute neuronal death was also observed in the CA1 of the wild-type mice. These results suggest that GLT-1 takes up extracellular glutamate to protect neurons in early stage of ischemia and then releases glutamate, triggering acute neuronal death, when ischemic conditions are elongated. The function of GLT-1 may change from neuroprotective to neurodegenerative during ischemia. The glutamate levels in mice lacking EAAC1 were significantly lower than the corresponding glutamate levels in wild-type mice during ischemia. This result suggests that EAAC1 releases glutamate immediately after ischemia. EAAC1 may act neurodegeneratively from the early stage of ischemia.