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The Journal of Neuroscience, August 6, 2003, 23(18):7176-7182

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Functional Changes of Glial Glutamate Transporter GLT-1 during Ischemia: An In Vivo Study in the Hippocampal CA1 of Normal Mice and Mutant Mice Lacking GLT-1

Akira Mitani¹ and Kohichi Tanaka^2,3

¹College of Medical Technology, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan, ²Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8579, Japan, and ³Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan

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) during brain ischemia by using an in vivo brain microdialysis technique in GLT-1 mutant mice. A microdialysis probe was placed in the hippocampal CA1 of GLT-1 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 wild-type mice. These results suggest that GLT-1 takes up extracellular glutamate to protect neurons in the 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.

Key words: glutamate transporter; glia; GLT-1; knock-out mouse; hippocampal CA1; ischemia; neuronal death; microdialysis

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Received Mar. 17, 2003; revised Jun. 5, 2003; accepted Jun. 12, 2003.

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