Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen

Estrogen influences neuronal development and a broad spectrum of neural functions. In addition, several lines of evidence suggest a role as neuroprotective factor for estrogen in the CNS. Neuroprotection can result from direct estrogen-neuron interactions or be mediated indirectly involving the regulation of physiological properties of nonneuronal cells, such as astrocytes and microglia. Increased L-glutamate levels are associated with neurotoxic and neurodegenerative processes in the brain. Thus, the removal of L-glutamate from the extracellular space by astrocytes through the astroglial glutamate transporters GLT-1 and GLAST appears essential for maintaining a homeostatic milieu for neighboring neurons. We have therefore studied the influence of 17 beta-estradiol on (L)-glutamate metabolism in cultured astrocytes from the neonate mouse midbrain using quantitative RT-PCR and Western blotting for both transporters as well as functional L-glutamate uptake studies. The administration of estrogen significantly increased the expression of GLT-I and GLAST on the mRNA and protein level. Likewise, Specific L-glutamate uptake by astrocytes was elevated after estrogen exposure and mimicked by dbcAMP stimulation. Induction of transporter expression and L-glutamate uptake were sensitive to ICI 182,780 treatment suggesting estrogen action through nuclear estrogen receptors. These findings indicate that estrogen can prevent L-glutamate-related cell death by decreasing extracellular L-glutamate levels through an increased L-glutamate uptake capacity by astrocytes. (c) 2004 Elsevier B.V. All rights reserved.