CHARACTERIZATION OF THE EFFECTS OF LITHIUM AND INOSITOL ON PHOSPHOINOSITIDE TURNOVER IN CEREBELLAR GRANULE CELLS IN PRIMARY CULTURE

The effect of lithium on inositol phospholipid resynthesis in primary cultures of cerebellar granule cells was studied. During activation of phospholipase C by the combined action of a muscarinic agonist and mi ld depolarization, the levels of inositol phospholipids as well as the inositol phospholipid precursor CMP-phosphatidate appeared highly sen sitive to lithium with half-maximal accumulation of CMP-phosphatidate attained at 0.5 mM LiCl, a concentration close to that in the plasma o f patients subjected to lithium therapy, Under the same conditions, th e effect of lithium on inositol phospholipid metabolism appeared to be mediated by depletion of cytoplasmic free inositol content, This was indicated by the observation that preincubation for 48 h in high extra cellular inositol concentrations could decrease or delay the depletion of inositol phospholipids and the accumulation of CMP-phosphatidate i nduced by 10 mM LiCl. Because even relatively high concentrations of e xtracellular inositol (500 mu M) only partially prevented inositol pho spholipid depletion, cerebellar granule cells appear to have a compara tively low capacity to accumulate inositol intracellularly, in compari son with other brain cells in culture. The relationship between CMP-ph osphatidate accumulation and phospholipase C activity has also been in vestigated using a range of agonists that have been reported to act on cerebellar granule cells.