PT - JOURNAL ARTICLE AU - Hrvoje Augustin AU - Yael Grosjean AU - Kaiyun Chen AU - Qi Sheng AU - David E. Featherstone TI - Nonvesicular Release of Glutamate by Glial xCT Transporters Suppresses Glutamate Receptor Clustering <em>In Vivo</em> AID - 10.1523/JNEUROSCI.4770-06.2007 DP - 2007 Jan 03 TA - The Journal of Neuroscience PG - 111--123 VI - 27 IP - 1 4099 - http://www.jneurosci.org/content/27/1/111.short 4100 - http://www.jneurosci.org/content/27/1/111.full SO - J. Neurosci.2007 Jan 03; 27 AB - We hypothesized that cystine/glutamate transporters (xCTs) might be critical regulators of ambient extracellular glutamate levels in the nervous system and that misregulation of this glutamate pool might have important neurophysiological and/or behavioral consequences. To test this idea, we identified and functionally characterized a novel Drosophila xCT gene, which we subsequently named “genderblind” (gb). Genderblind is expressed in a previously overlooked subset of peripheral and central glia. Genetic elimination of gb causes a 50% reduction in extracellular glutamate concentration, demonstrating that xCT transporters are important regulators of extracellular glutamate. Consistent with previous studies showing that extracellular glutamate regulates postsynaptic glutamate receptor clustering, gb mutants show a large (200–300%) increase in the number of postsynaptic glutamate receptors. This increase in postsynaptic receptor abundance is not accompanied by other obvious synaptic changes and is completely rescued when synapses are cultured in wild-type levels of glutamate. Additional in situ pharmacology suggests that glutamate-mediated suppression of glutamate receptor clustering depends on receptor desensitization. Together, our results suggest that (1) xCT transporters are critical for regulation of ambient extracellular glutamate in vivo; (2) ambient extracellular glutamate maintains some receptors constitutively desensitized in vivo; and (3) constitutive desensitization of ionotropic glutamate receptors suppresses their ability to cluster at synapses.