title: Regulation of hippocampal synaptic strength by glial xCT.
abstract: Most extracellular glutamate in the brain is released by xCT, a glial antiporter that exports glutamate and imports cystine. The function of xCT, and extracellular glutamate in general, remains unclear. Several lines of evidence suggest that glutamate from xCT could act in a paracrine fashion to suppress glutamatergic synapse strength by triggering removal of postsynaptic glutamate receptors. To test this idea, we used whole-cell patch-clamp electrophysiology and immunohistochemistry to quantify receptor number and synapse function in xCT knock-out mouse hippocampal CA3-CA1 synapses. Consistent with the hypothesis that xCT suppresses glutamate receptor number and synapse strength, xCT knock-out synapses showed increased AMPA receptor abundance with concomitant large enhancements of spontaneous and evoked synaptic transmission. We saw no evidence for changes in GABA receptor abundance or the overall number of glutamatergic synapses. The xCT knock-out phenotype was replicated by incubating slices in the xCT inhibitor (S)-4-carboxyphenylglycine, and consistent with the idea that xCT works by regulating extracellular glutamate, the xCT knock-out phenotype could be reproduced in controls by incubating the slices in glutamate-free aCSF. We conclude that glutamate secreted via xCT suppresses glutamatergic synapse strength by triggering removal of postsynaptic AMPA receptors.
authors.affiliation: Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois 60607.
authors.forename: Leena E
authors.identifier: http://orcid.org/0000-0001-5534-7608
authors.initials: LE
authors.lastname: Williams
authors.affiliation: Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois 60607 def@uic.edu.
authors.forename: David E
authors.identifier: http://orcid.org/0000-0002-7151-8507
authors.initials: DE
authors.lastname: Featherstone
mesh_terms: D027182:Amino Acid Transport System y+ / Q000502:physiology*; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000502:physiology*; D009924:Organ Culture Techniques; D013569:Synapses / Q000502:physiology*
chemical_list: D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse
keywords: glutamate; synaptic; xCT