CONICET | Buscador de Institutos y Recursos Humanos

Lithium has been widely used as long-term mood stabilizer in the treatment of bipolar and depressive disorders. Lithium exerts neuroprotective, anti-inflammatory and anti-apoptotic properties. It also controls lineage specification, proliferation and differentiation of varied cell types through the modulation of intracellular signaling systems such as Akt/GSK3 and Wnt/β-catenin. Because these pathways are required for both Schwann cell (SC) proliferation and differentiation, we performed a comprehensive study of the potential effects of lithium on the proliferation and differentiation of SCs using a variety of in vitro systems. Surprisingly, we found that lithium specifically and reversibly prevented Schwann cell mitogenesis when administered in conjunction with growth factors such as neuregulin. Prolonged lithium treatment promoted cell enlargement and a growth arrested state without inducing the expression of myelin-related markers such as galactocerebroside (O1) and protein zero (P0). When lithium was administered in combination with cAMP, an instructive signal for SC differentiation, it inhibited the expression of Krox-20, a master regulator of the myelinating phenotype, and that of O1 and P0 in a dose dependent, specific and reversible manner. Likewise, lithium suppressed myelin sheath formation in co-cultures of SCs and dorsal root ganglion neurons without inducing myelin loss or dedifferentiation. SCs responded to lithium by phosphorylating GSK3β on Ser-9, and pharmacological inhibition of GSK3β activity was sufficient to mimic lithium?s effects on differentiation. In summary, lithium not only halts SC proliferation but also exerts a GSK3β-dependent antagonistic action on the early transcriptional control of differentiation leading to myelin formation.