PROSTAGLANDINS STIMULATE CALCIUM-DEPENDENT GLUTAMATE RELEASE IN ASTROCYTES

Astrocytes in the brain form an intimately associated network with neu rons. They respond to neuronal activity and synaptically released glut amate by raising intracellular calcium concentration ([Ca2+](i))(1,2), which could represent the start of back-signalling to neurons(3-5). H ere we show that coactivation of the AMPA/kainate and metabotropic glu tamate receptors (mGluRs) on astrocytes stimulates these cells to rele ase glutamate through a Ca2+-dependent process mediated by prostagland ins. Pharmacological inhibition of prostaglandin synthesis prevents gl utamate release, whereas application of prostaglandins (in particular PGE(2)) mimics and occludes the releasing action of GluR agonists. PGE (2) promotes Ca2+-dependent glutamate release from cultured astrocytes and also from acute brain slices under conditions that suppress neuro nal exocytotic release. When applied to the CA1 hippocampal region, PG E(2) induces increases in [Ca2+](i) both in astrocytes and in neurons. The [Ca2+](i) increase in neurons is mediated by glutamate released f rom astrocytes, because it is abolished by GluR antagonists. Our resul ts reveal a new pathway of regulated transmitter release from astrocyt es and outline the existence of an integrated glutamatergic cross-talk between neurons and astrocytes in situ that may play critical roles i n synaptic plasticity and in neurotoxicity.