Lithium reversibly inhibits Schwann cell proliferation and differentiation without inducing myelin loss or dedifferentiation

RANDALL BERG; PATRICIA SETTON-AVRUJ ; GONZALO PIÑERO ; NATALIA ANDERSEN; JENIFER SOTO; PAULA MONJE

Denver, Colorado

Congreso; American Society for Neurochemistry 47th Annual Meeting; 2016

American Society for Neurochemistry

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 intracelullar signaling systems such as Akt/GSK3 and Wnt/beta-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. Surprinsingly, we found that lithium specifically and reversibly prevented Schwann cell mitogenesis when administred in conjuntion 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 myelinationg phenotype, and that O1 and P0 in a dose dependent, specific and reversible manner. Likewise, lithium suppresed myelin sheat formation in co-cultures of SCs and dorsal root ganglion neurons without inducing myelin loss or dedifferentiation. SCs responded to lithium by phosphorylating GSK3beta on Ser-9, and pharmacological inhibition of GSK3beta activity was sufficient to mimic lithium´s effects on differentiation. In summary, lithium not only halts SC proliferation but also exerts a GSK3beta-dependent antagonistic action on the early transcriptional control of differentiation leading to myelin formation.