Relation of cholesterol to astrocytic differentiation in C-6 glial cells

The relation of cellular cholesterol content to a biochemical expression of astrocytic differentiation was investigated in cultured C-6 glial cells. The astrocytic marker, glutamine synthetase, was studied. Cellular sterol content was perturbed with compactin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase and, thereby, cholesterol biosynthesis. Depletion of cellular sterol resulted in 72 h in a more than twofold increase in glutamine synthetase activity. Production of various degrees of sterol depletion with different concentrations of compactin demonstrated a striking inverse relationship between glutamine synthetase activity and the cellular sterol/phospholipid molar ratio. That the effect of compactin, in fact, is mediated by depletion of sterol was shown further by prevention of the compactin-induced increase in synthetase activity by simultaneous addition of exogenous cholesterol. Moreover, addition of cholesterol alone to the culture medium led to both a decrease in glutamine synthetase activity and an increase in the sterol/phospholipid molar ratio. The possibility that the compactin-induced increase in glutamine synthetase activity is caused by an increase in synthesis of the enzyme was suggested by prevention of the increase by cycloheximide. The data suggest that astrocytic differentiation is stimulated by a decrease in cellular sterol content. When considered with our previous observation that oligodendroglial differentiation is inhibited by such a decrease, the findings suggest that cellular sterol content is a critical determinant of the direction of glial differentiation, i.e., whether along astrocytic or oligodendroglial lines.