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J. Biol. Chem., Vol. 280, Issue 41, 34924-34932, October 14, 2005

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Differential Promotion of Glutamate Transporter Expression and Function by Glucocorticoids in Astrocytes from Various Brain Regions^*

Jürgen Zschocke, Nadhim Bayatti, Albrecht M. Clement, Heidrun Witan, Maciej Figiel, Jürgen Engele, and Christian Behl1

From the Department of Pathobiochemistry, Johannes Gutenberg University Mainz, 55099 Mainz, Germany and Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany

Steroids that activate glucocorticoid receptors (GRs) and mineralocorticoid receptors have important regulatory effects on neural development, plasticity, and the body's stress response. Here, we investigated the role of corticosteroids in regulating the expression of the glial glutamate transporters glial glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in rat primary astrocytes. The synthetic glucocorticoid dexamethasone provoked a marked increase of GLT-1 transcription and protein levels in cortical astrocytes, whereas GLAST expression remained unaffected. Up-regulation of GLT-1 expression was accompanied by an enhanced glutamate uptake, which could be blocked by the specific GLT-1 inhibitor dihydrokainate. The promoting effect of dexamethasone on GLT-1 gene expression and function was abolished by the GR antagonist mifepristone. A predominant role of the GR was further supported by the observation that corticosterone could elevate GLT-1 expression in a dose-dependent manner, whereas aldosterone, the physiological ligand of the mineralocorticoid receptor, exerted only weak effects even when applied at high concentrations. Moreover, we monitored brain region-specific differences, since all corticosteroids used in this study failed to alter the expression of GLT-1 in midbrain and cerebellar glia, although expression levels of both corticosteroid receptor subtypes were similar in all brain regions analyzed. Dexamethasone, however, modestly enhanced GLT-1 expression in cerebellar glia in combination with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine, suggesting that suppression of GLT-1 expression in cerebellar cultures may at least in part be epigenetically mediated by a DNA methylation-dependent process. Taken together, our data highlight a potential role for glucocorticoids in regulating GLT-1 gene expression during central nervous system development or pathophysiogical processes including stress.

Received for publication, March 8, 2005 , and in revised form, June 21, 2005.

^* This project was supported in part by a grant of the Peter-Beate-Heller Foundation (to C. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Institute for Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, Medical School, 55099 Mainz, Germany. Tel.: 49-6131-39-25890; Fax: 49-6131-39-25792; E-mail: cbehl{at}uni-mainz.de.

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