Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation

Abstract

Neural stem cells give rise to new hippocampal neurons throughout adulthood, and defects in neurogenesis may predispose an individual to mood disorders, such as major depression. Our understanding of the signals controlling this process is limited, so we explored potential pathways regulating adult hippocampal progenitor (AHP) proliferation and neuronal differentiation. We demonstrate that the mood stabilizer lithium directly expands pools of AHPs in vitro, and induces them to become neurons at therapeutically relevant concentrations. We show that these effects are independent of inositol monophosphatase, but dependent on Wnt pathway components. Both downregulation of glycogen synthase kinase-3b, a lithiumsensitive component of the canonical Wnt signaling pathway, and elevated b-catenin, a downstream component of the same pathway produce effects similar to lithium. In contrast, RNAi-mediated inhibition of b-catenin abolishes the proliferative effects of lithium, suggesting that Wnt signal transduction may underlie lithium's therapeutic effect. Together, these data strengthen the connection between psychopharmacologic treatment and the process of adult neurogenesis, while also suggesting the pursuit of modulators of Wnt signaling as a new class of more effective mood stabilizers/antidepressants.

Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia–Ischemia is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells

“…Possible mechanisms favoring neuronal differentiation may involve the BDNF pathway (Su et al, 2009), ERK-and CREBdependent pathways (Kim et al, 2004), as well as the Wnt pathway (Wexler et al, 2008). However, in this study, the proportion of neuronal and astrocyte differentiation was not different between the lithium and vehicle groups.…”

“…The number of BLBP-positive cells was not increased by lithium treatment in control animals, indicating that lithium stimulated proliferation of progenitor cells rather than the asymmetric division of stem cells. Wexler reported that lithium enhances cell proliferation by activating the canonical Wnt pathway (Wexler et al, 2008). GSK-3b is a critical mediator of the Wnt/bcatenin signaling pathway and lithium inhibits the activation of GSK-3b directly and indirectly (Chalecka-Franaszek and Chuang, 1999;Li et al, 2010).…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…inhibitor lithium chloride (LiCl), which stabilizes and activates β-catenin, induces adult hippocampal progenitor cell proliferation [132]. LiCl treatment also stimulates cell proliferation and neuronal fate specification in a mouse model of Alzheimer's disease [133].…”

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

“…We also showed that agomelatine increases the phosphorylation of ERK1/2, AKT, and GSK3b known to transduce the effects of antidepressant agent and mood stabilizers on proliferation of hippocampal neural progenitors (Jiang et al, 2005;Wexler et al, 2008;Silva et al, 2008). The enhanced survival of new granule cells may also be related to the activation of MAPK (ERK1/2) and PI-3K signaling pathways, as previously shown in vitro (Almeida et al, 2005), and hippocampal NSCs can be protected from apoptosis by antidepressant-induced activation of BDNF and the MAPK pathway (Peng et al, 2008).…”