ALKYLPHOSPHOCHOLINES INHIBIT CHOLINE UPTAKE AND PHOSPHATIDYLCHOLINE BIOSYNTHESIS IN RAT SYMPATHETIC NEURONS AND IMPAIR AXONAL EXTENSION

At least 50% of the major axonal membrane lipid, phosphatidylcholine, of rat sympathetic neurons is synthesized in situ in axons [Posse de C haves, Vance, Campenot and Vance (1995) J. Cell Biol. 128, 913-918]. I n the same study we reported that, in a choline-deficient model for ne uron growth, phosphatidylcholine synthesis in cell bodies is neither n ecessary nor sufficient for growth of distal axons. Rather, the local synthesis of phosphatidylcholine in distal axons is required for norma l axon growth. We have now used three alkylphosphocholines (hexadecylp hosphocholine, dodecylphosphocholine and octadecylphosphocholine) as i nhibitors of PtdCho biosynthesis in a compartmented model for culture of rat sympathetic neurons. The experiments reveal that alkylphosphoch olines decrease the uptake of choline into these neurons and inhibit P tdCho synthesis, but not via an effect on the activity of the enzyme C TP: phosphocholine cytidylyltransferase. We also show that when the di stal axons, but not the cell bodies, are exposed to alkylphosphocholin es, axonal elongation is inhibited, which is consistent with the hypot hesis that phosphatidylcholine synthesis in axons, but not in cell bod ies, is required for axonal elongation. The inhibitory effect of alkyl phosphocholines on axon growth is most likely not mediated via a decre ase in the activity of protein kinase C, since when this enzyme activi ty is down-regulated by treatment of the cells with phorbol ester, the alkylphosphocholines retain their ability to inhibit axonal growth.