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Volume 17, Number 3, Issue of February 1, 1997 pp. 932-940
Copyright ©1997 Society for Neuroscience

Neuronal Regulation of Glutamate Transporter Subtype Expression in Astrocytes

Received July 11, 1996; revised Oct. 30, 1996; accepted Nov. 7, 1996.

Raymond A. Swanson¹, Jialing Liu¹, Johann W. Miller¹, Jeffrey D. Rothstein², Kevin Farrell¹, Becky A. Stein¹, and Maria C. Longuemare¹

¹ Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, and ² Deparment of Neuroscience, The Johns Hopkins Medical Center, Baltimore, Maryland 21287

GLT-1, GLAST, and EAAC1 are high-affinity, Na⁺-dependent glutamate transporters identified in rat forebrain. The expression of these transporter subtypes was characterized in three preparations: undifferentiated rat cortical astrocyte cultures, astrocytes cocultured with cortical neurons, and astrocyte cultures differentiated with dibutyryl cyclic AMP (dBcAMP). The undifferentiated astrocyte monocultures expressed only the GLAST subtype. Astrocytes cocultured with neurons developed a stellate morphology and expressed both GLAST and GLT-1; neurons expressed only the EAAC1 transporter, and rare microglia in these cultures expressed GLT-1. Treatment of astrocyte cultures with dBcAMP induced expression of GLT-1 and increased expression of GLAST. These effects of dBcAMP on transporter expression were qualitatively similar to those resulting from coculture with neurons, but immunocytochemistry showed the pattern of transporter expression to be more complex in the coculture preparations. Compared with astrocytes expressing only GLAST, the dBcAMP-treated cultures expressing both GLAST and GLT-1 showed an increase in glutamate uptake V_max, but no change in the glutamate K_m and no increased sensitivity to inhibition by dihydrokainate. Pyrrolidine-2,4-dicarboxylic acid and threo--hydroxyaspartic acid caused relatively less inhibition of transport in cultures expressing both GLAST and GLT-1, suggesting a weaker effect at GLT-1 than at GLAST. These studies show that astrocyte expression of glutamate transporter subtypes is influenced by neurons, and that dBcAMP can partially mimic this influence. Manipulation of transporter expression in astrocyte cultures may permit identification of factors regulating the expression and function of GLAST and GLT-1 in their native cell type.

Key words: dibutyryl cAMP; dihydrokainate; GLT-1; threo--hydroxyaspartate; glutamate uptake; PDC; pyrrolidine-2,4-dicarboxylate; microglia; GLAST

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