Choline release and inhibition of phosphatidylcholine synthesis precede excitotoxic neuronal death but not neurotoxicity induced by serum deprivation

N-Methyl-D-aspartate (NMDA) receptor overactivation has been proposed to in duce excitotoxic neuronal death by enhancing membrane phospholipid degradat ion. In previous studies, we have shown that NMDA releases choline and redu ces membrane phosphatidylcholine in vivo. We now observed that glutamate an d NMDA induce choline release in primary neuronal cortical cell cultures. T his effect is Ca2+-dependent and is blocked by MK-801 ((+)5-methyl-10,11-di hydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate). In cortical neurons, the NMDA receptor-mediated choline release precedes excitotoxic ce ll death but not neuronal death induced by either osmotic lysis or serum de privation. Glutamate, at concentrations that release arachidonic acid, does not release choline in cerebellar granule cells, unless these cells are re ndered susceptible to excitotoxic death by energy deprivation. The NMDA-evo ked release of choline is not mediated by phospholipases A(2) or C. Moreove r, NMDA does not activate phospholipase D in cortical cells. However, NMDA inhibits incorporation of [methyl-H-3]choline into both membrane phosphatid ylcholine and sphingomyelin. These results show that the increase in extrac ellular choline induced by NMDA receptor activation is directly related wit h excitotoxic cell death and indicate that choline release is an early even t of the excitotoxic process produced by inhibition of phosphatidylcholine synthesis and not by activation of membrane phospholipid degradation.