PLATELET-DERIVED GROWTH-FACTOR INDUCES A LONG-TERM INHIBITION OF N-METHYL-D-ASPARTATE RECEPTOR FUNCTION

Platelet-derived growth factor (PDGF) is a multifunctional protein tha t plays important roles in many tissues, including the mammalian centr al nervous system. PDGF and PDGF receptors (PDGFRs) are expressed in v irtually every region of the central nervous system where they are inv olved in the development, survival, growth, and differentiation of bot h neuronal and glial cells. We now report that a brief activation of P DGFRs produced a long-lasting inhibition of N-methyl-D-aspartate (NMDA ) dependent excitatory postsynaptic currents in CA1 pyramidal neurons in rat hippocampal slices. PDGF also inhibited NMDA receptors (NMDA-Rs ) in cultured hippocampal neurons by a mechanism that involves a decre ase in single channel open probability. Non-NMDA receptor function was not affected by PDGF in hippocampal neurons. Experiments with mutant PDGFRs and chelation of intracellular Ca2+ in Xenopus oocytes indicate that this inhibition depends on a phospholipase C-gamma-induced eleva tion of intracellular Ca2+ levels. The PDGF-induced inhibition of NMDA -Rs is produced by a mechanism different than the well characterized p henomenon of Ca2+-dependent NMDA-R run down because the effect of PDGF was blocked by the phosphatase inhibitor, calyculin A, and was not af fected by the microtubule polymerizing agent, phalloidin. Because elev ations of PDGF levels are associated with neurological trauma or disea se, we propose that PDGF can exert neuroprotective effects by inhibiti ng NMDA-R-dependent excitotoxicity.