Regulation of Mouse Hippocampal Synaptic Transmission by Glial xCT

xCT is a glial transporter protein that exports substantial amounts of glutamate into the extracellular fluid. Previous studies in Drosophila and rats suggest that xCT suppresses glutamatergic synapse strength, possibly by triggering downregulation of postsynaptic glutamate receptors. Other behavioral observations in mice link xCT to hippocampal function. We therefore analyzed hippocampal CA3-CA1 synapses in xCT -/- mutant mice, to test whether glutamate receptor abundance and synapse strength are altered. Whole cell patch clamp electrophysiology and immunohistochemistry revealed that xCT -/- mutant mouse synapses do indeed contain many more functional postsynaptic receptors, and doubled synapse strength. We found no evidence for an increase in GABA receptors or change in overall synapse number. Consistent with the idea that xCT suppresses glutamate receptor number by maintaining extracellular glutamate levels; the xCT mutant synapse phenotype was replicated by incubation of hippocampal slices in artificial cerebrospinal fluid containing no glutamate. We conclude that xCT is a very strong previously unrecognized regulator of hippocampal synapse strength, with possibly critical roles in plasticity