Functional changes of glutamate transporters during ischemia.

谷氨酸转运体将谷氨酸从细胞外空间中移除，并在正常情况下将其维持在神经毒性水平以下。然而，在缺血条件下的动力学仍有待确定。在本研究中，我们利用在体脑微透析技术，对脑缺血时胶质细胞谷氨酸转运体(GLT-1)和神经元谷氨酸转运体(EAAC1)的功能进行了研究。将微透析探针放置在突变小鼠和野生型小鼠的海马CA1区，并在缺血5分钟和20分钟期间测量谷氨酸水平。在缺血5分钟时，缺乏GLT-1的小鼠的谷氨酸水平显著高于野生型小鼠相应的谷氨酸水平。缺乏GLT-1的小鼠CA1区可诱导迟发性神经元死亡，而野生型小鼠的CA1区未见神经元迟发性死亡。当缺血时间延长至20min时，野生型小鼠的谷氨酸水平显著高于缺GLT-1组小鼠在最后12.5min的谷氨酸水平。野生型小鼠CA1区也可见急性神经元死亡。这些结果表明，GLT-1在缺血早期摄取细胞外谷氨酸来保护神经元，然后释放谷氨酸，当缺血条件延长时，触发神经元的急性死亡。缺血时GLT-1的功能可能由神经保护转变为神经退行性改变。在缺血期间，缺乏EAAC1的小鼠的谷氨酸水平显著低于野生型小鼠的相应谷氨酸水平。这一结果表明，EAAC1在缺血后立即释放谷氨酸。EAAC1可能从缺血早期起就表现为神经退行性改变。

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.