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The Journal of Neuroscience, June 20, 2007, 27(25):6607-6619; doi:10.1523/JNEUROSCI.0790-07.2007

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Cellular/Molecular
Variations in Promoter Activity Reveal a Differential Expression and Physiology of Glutamate Transporters by Glia in the Developing and Mature CNS

Melissa R. Regan,¹ Yanhua H. Huang,² Yu Shin Kim,² Margaret I. Dykes-Hoberg,¹ Lin Jin,¹ Andrew M. Watkins,¹ Dwight E. Bergles,² and Jeffrey D. Rothstein^1,2

¹Department of Neurology and ²The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21287

Correspondence should be addressed to either of the following: Dr. Jeffrey D. Rothstein, Department of Neurology, Johns Hopkins University, 600 North Wolfe Street, Meyer 6-109, Baltimore, MD 21287, Email: jrothstein{at}jhmi.edu; or Dr. Dwight E. Bergles, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, 725 North Wolfe Street, Wood Basic Science Building 813, Baltimore, MD 21205, Email: dbergles{at}jhmi.edu. Material requests should be e-mailed to Email: jrothstein{at}jhmi.edu

Glutamate transporters regulate excitatory neurotransmission and prevent glutamate-mediated excitotoxicity in the CNS. To better study the cellular and temporal dynamics of the expression of these transporters, we generated bacterial artificial chromosome promoter Discosoma red [glutamate–aspartate transporter (GLAST)] and green fluorescent protein [glutamate transporter-1 (GLT-1)] reporter transgenic mice. Analysis of these mice revealed a differential activation of the transporter promoters not previously appreciated. GLT-1 promoter activity in the adult CNS is almost completely restricted to astrocytes, often and unexpectedly in a nonoverlapping pattern with GLAST. Spinal cord GLT-1 promoter reporter, protein density, and physiology were 10-fold lower than in brain, suggesting a possible mechanism for regional sensitivity seen in disease. The GLAST promoter is active in both radial glia and many astrocytes in the developing CNS but is downregulated in most astrocytes as the mice mature. In the adult CNS, the highest GLAST promoter activity was observed in radial glia, such as those located in the subgranular layer of the dentate gyrus. The continued expression of GLAST by these neural progenitors raises the possibility that GLAST may have an unanticipated role in regulating their behavior. In addition, GLAST promoter activation was observed in oligodendrocytes in white matter throughout many (e.g., spinal cord and corpus callosum), but not all (e.g., cerebellum), CNS fiber tracts. Overall, these studies of GLT-1 and GLAST promoter activity, protein expression, and glutamate uptake revealed a close correlation between transgenic reporter signals and uptake capacity, indicating that these mice provide the means to monitor the expression and regulation of glutamate transporters in situ.

Key words: BAC; glutamate; GLT-1; GLAST; membrane; transgenic; oligodendroglial; astroglia

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Received Feb. 21, 2007; revised May 7, 2007; accepted May 7, 2007.

Correspondence should be addressed to either of the following: Dr. Jeffrey D. Rothstein, Department of Neurology, Johns Hopkins University, 600 North Wolfe Street, Meyer 6-109, Baltimore, MD 21287, Email: jrothstein{at}jhmi.edu; or Dr. Dwight E. Bergles, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, 725 North Wolfe Street, Wood Basic Science Building 813, Baltimore, MD 21205, Email: dbergles{at}jhmi.edu. Material requests should be e-mailed to Email: jrothstein{at}jhmi.edu

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