DISRUPTION BY LITHIUM OF PHOSPHOINOSITIDE SIGNALING IN CEREBELLAR GRANULE CELLS IN PRIMARY CULTURE

Mild depolarisation (20 mM KCl) synergistically enhances the ability o f a muscarinic agonist to activate phosphoinositide turnover and to el evate inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] in cerebellar granu le cells in primary culture. The effects of lithium on this intense st imulation of phosphoinositide turnover was studied, Lithium causes dep letion of cytoplasmic inositol and phosphoinositides, which results in the inhibition of phosphoinositide turnover within 15 min and the ret urn of Ins(1,4,5)P-3 to basal levels at this time, This inhibition cou ld not be reversed by culturing and preincubating cerebellar granule c ells in concentrations of inositol similar to those detected in the CS F, Inositol concentrations substantially in excess of those in the CSF not only reversed the effects of lithium on stimulated Ins(1,4,5)P-3 levels, but significantly enhanced this level in comparison with stimu lation in the absence of lithium. sn-1,2-Diacylglycerol elevation duri ng stimulated phosphoinositide turnover was also disrupted by lithium, but in contrast to Ins(1,4,5)(3), the presence of lithium resulted in a transient enhancement of the elevation evoked by carbachol plus mil d KCl depolarisation, which was reversed by 500 mu M inositol, but not by 200 mu M inositol, The implications oi these phenomena in relation to the mechanism of action of lithium in the treatment of manic depre ssion are discussed.