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Reversed Actrocytic GLT-1 during Ischemia is Crucial to Excitotoxic Death of Neurons, but Contributes to the Survival of Astrocytes themselves

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Abstract

During ischemia, the operation of astrocytic/neuronal glutamate transporters is reversed and glutamate and Na+ are co-transported to the extracellular space. This study aims to investigate whether this reversed operation of glutamate transporters has any functional meanings for astrocytes themselves. Oxygen/glucose deprivation (OGD) of neuron/astrocyte co-cultures resulted in the massive death of neurons, and the cell death was significantly reduced by treatment with either AP5 or DHK. In cultured astrocytes with little GLT-1 expression, OGD produced Na+ overload, resulting in the reversal of astrocytic Na+/Ca2+-exchanger (NCX). The reversed NCX then caused Ca2+ overload leading to the damage of astrocytes. In contrast, the OGD-induced Na+ overload and astrocytic damage were significantly attenuated in PACAP-treated astrocytes with increased GLT-1 expression, and the attenuation was antagonized by treatment with DHK. These results suggested that the OGD-induced reversal of GLT-1 contributed to the survival of astrocytes themselves by releasing Na+ with glutamate via reversed GLT-1.

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Abbreviations

AP5:

DL-2-Amino-5-phosphonopentanoic acid, a specific inhibitor of NMDA type glutamate receptors

CM:

Conditioned medium from cells cultured for more than 2 weeks

DHK:

Dihydrokainate, a specific blocker of GLT-1

EBSS:

Earl’s balanced salt solution

GFAP:

Glial fibrillary acidic protein

LDH:

Lactate dehydrogenase

MAP2:

Microtubule-associated protein 2

NCX:

Na+/Ca2+-exchanger

NADH:

Nicotinamide adenine dinucleotide

OGD:

Oxygen/glucose deprivation

PACAP:

Pituitary adenylate cyclase-activating polypeptide

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Acknowledgment

The authors wish to thank Dr. Takayuki Nakajima, Research Institute for Electronic Science, Hokkaido University, for advice on the immunostaining of cortical cultures.

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  1. Laboratory of Cellular Cybernetics, Graduate School of Information Science and Technology, Hokkaido University, Sapporo, 060-0814, Japan

    Tatsuro Kosugi & Koichi Kawahara

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  1. Tatsuro Kosugi
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  2. Koichi Kawahara
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Correspondence to Koichi Kawahara.

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Kosugi, T., Kawahara, K. Reversed Actrocytic GLT-1 during Ischemia is Crucial to Excitotoxic Death of Neurons, but Contributes to the Survival of Astrocytes themselves. Neurochem Res 31, 933–943 (2006). https://doi.org/10.1007/s11064-006-9099-6

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  • DOI: https://doi.org/10.1007/s11064-006-9099-6

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