Prostaglandins stimulate calcium-dependent glutamate release in astrocytes

Astrocytes in the brain form an intimately associated network with neurons. They respond to neuronal activity and synaptically released glutamate by raising intracellular calcium concentration ([Ca 2+ ] i ) 1 , 2 which could represent the start of back-signalling to neurons 3 , 4 , 5 . Here we show that coactivation of the AMPA/kainate and metabotropic glutamate receptors (mGluRs) on astrocytes stimulates these cells to release glutamate through a Ca 2+ -dependent process mediated by prostaglandins. Pharmacological inhibition of prostaglandin synthesis prevents glutamate release, whereas application of prostaglandins (in particular PGE 2 ) mimics and occludes the releasing action of GluR agonists. PGE 2 promotes Ca 2+ -dependent glutamate release from cultured astrocytes and also from acute brain slices under conditions that suppress neuronal exocytotic release. When applied to the CA1 hippocampal region, PGE 2 induces increases in [Ca 2+ ] i both in astrocytes and in neurons. The [Ca 2+ ] i increase in neurons is mediated by glutamate released from astrocytes, because it is abolished by GluR antagonists. Our results reveal a new pathway of regulated transmitter release from astrocytes and outline the existence of an integrated glutamatergic cross-talk between neurons and astrocytes in situ that may play critical roles in synaptic plasticity and in neurotoxicity.