Immediate Early Gene c-fos in the Brain: Focus on Glial Cells

The c-fos gene was first described as a proto-oncogene responsible for the induction of bone tumors. A few decades ago, activation of the protein product c-fos was reported in the brain after seizures and other noxious stimuli. Since then, multiple studies have used c-fos as a brain activity marker. Although it has been attributed to neurons, growing evidence demonstrates that c-fos expression in the brain may also include glial cells. In this review, we collect data showing that glial cells also express this proto-oncogene. We present evidence demonstrating that at least astrocytes, oligodendrocytes, and microglia express this immediate early gene (IEG). Unlike neurons, whose expression changes used to be associated with depolarization, glial cells seem to express the c-fos proto-oncogene under the influence of proliferation, differentiation, growth, inflammation, repair, damage, plasticity, and other conditions. The collected evidence provides a complementary view of c-fos as an activity marker and urges the introduction of the glial cell perspective into brain activity studies. This glial cell view may provide additional information related to the brain microenvironment that is difficult to obtain from the isolated neuron paradigm. Thus, it is highly recommended that detection techniques are improved in order to better differentiate the phenotypes expressing c-fos in the brain and to elucidate the specific roles of c-fos expression in glial cells.