Myelin gene activation: a glucose sensitive critical period in development

Glucose deprivation was employed to model caloric undernutrition in newborn rat mixed glial cultures. Six day-old cultures were placed in serum-free media containing glucose concentrations from 0.55 mg/ml to 10 mg/ml. The expression of the myelin PLP, BP, and MAG genes was determined by Northern blot analysis. The activation of the myelin genes began at approximately 6 days in vitro (DIV), and a period of rapid upregulation followed through 14 DIV. The gene activity was directly related to the glucose concentration. The increase in glucose concentration from 0.55 to 1.5 mg/ml (which spans the physiological range) resulted in 2-3 fold increases in expression of the myelin genes, whereas further increases in glucose (2-10 mg/ml) produced only slight additional elevation in the gene activity. We used high glucose (5-6 mg/ml) as control, or low glucose (0.55 mg/ml) as deprived, to delineate possible critical periods of oligodendrocytic differentiation. Cultures were deprived for 4-day intervals, staggered from 6 to 22 DIV. Deprivation from 6 to 10 DIV produced an 80-90% suppression of the myelin gene upregulation at 22 DIV; deprivation from 10 to 14 DIV produced 60-70% suppression; whereas deprivation from 14 to 18 DIV was fully recoverable by 22 DIV. These results show that mixed glial cultures model the developmental pattern of myelin gene expression, as well as their vulnerability. Furthermore, the period of rapid upregulation of the myelin genes appears to be a critical period in development, during which glucose deprivation irreversibly alters oligodendrocyte differentiation.