Lithium Promotes Adult Neural Progenitor Differentiation Via GSK3ß- Dependent Signaling Pathways

Lithium is one of the standard drugs in the treatment of bipolar disorder, although its molecular modes of action are not well understood. It is a potent inhibitor of the multifunctional enzyme Glycogen Synthase Kinase 3ß (GSK3ß), which also plays a central role in neurogenesis via the developmental Wnt signaling pathway. In the present study, we analyzed the influence of lithium on GSK3ß signaling in adult neural progenitor cells (NPCs) from the rat subventricular zone. Protein expression patterns of NPCs cultured in the presence of 20 mM lithium chloride were compared to those of untreated cells. A proteomic approach based on two-dimensional gel electrophoresis and mass spectrometry showed changes in several GSK3ß-related proteins. We demonstrate the inhibition of GSK3ß by stabilization and nuclear transfer of its downstream target, ß-catenin. Moreover, the phosphorylated (=inhibited) GSK3ß protein was strongly enriched in the nuclear fraction of lithium-treated cells. The fraction of cells differentiated into astroglia increased moderately, and the fraction of cells differentiated into neurons increased strongly, as shown by immunostaining. In conclusion, lithium promotes NPC differentiation, mainly to neurons, via GSK3ß-related pathways.