Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC₅₀ for HDAC1 = 0.4 mm). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.

The canonical Wnt signaling pathway is critical for development of the mammalian central nervous system and regulates diverse processes throughout adulthood, including adult neurogenesis. Glycogen synthase kinase-3 (GSK-3) antagonizes the canonical Wnt pathway and therefore also plays a central role in neural development and adult neurogenesis. Lithium, the first line of therapy for bipolar disorder, inhibits GSK-3, activates Wnt signaling and stimulates adult neurogenesis, which may be important for its therapeutic effects. GSK-3 also regulates other critical signaling pathways which may contribute to the therapeutic effects of lithium, including growth factor/neurotrophin signaling downstream of Akt. Here we will review the roles of GSK-3 in CNS development and adult neurogenesis, with a focus on the canonical Wnt pathway. We will also discuss the validation of GSK-3 as the relevant target of lithium and the mechanisms downstream of GSK-3 that influence mammalian behavior.

Frizzled genes encode integral membrane proteins that function in multiple signal transduction pathways. They have been identified in diverse animals, from sponges to humans. The family is defined by conserved structural features, including seven hydrophobic domains and a cysteine-rich ligand-binding domain. Frizzled proteins are receptors for secreted Wnt proteins, as well as other ligands, and also play a critical role in the regulation of cell polarity. Frizzled genes are essential for embryonic development, tissue and cell polarity, formation of neural synapses, and the regulation of proliferation, and many other processes in developing and adult organisms; mutations in human frizzled-4 have been linked to familial exudative vitreoretinopathy. It is not yet clear how Frizzleds couple to downstream effectors, and this is a focus of intense study.

Hematopoietic stem cells are difficult to maintain in vitro, hampering their clinical use. Jian Huang et al. show that mouse and human hematopoietic stem cells can be maintained in culture in the absence of exogenous cytokines by combined treatment with agents that activate Wnt and inhibit mTOR signaling, two major signaling pathways implicated in stem cell homeostasis. Moreover, treatment with two such compounds used clinically increases the number of hematopoietic stem cells in mice in vivo. Hematopoietic stem cell (HSC) self renewal and lineage commitment depend on complex interactions with the microenvironment. The ability to maintain or expand HSCs for clinical applications or basic research has been substantially limited because these interactions are not well defined. Recent evidence suggests that HSCs reside in a low-perfusion, reduced-nutrient niche and that nutrient-sensing pathways contribute to HSC homeostasis. Here we report that suppression of the mTOR pathway, an established nutrient sensor, combined with activation of canonical Wnt–β-catenin signaling, allows for the ex vivo maintenance of human and mouse long-term HSCs under cytokine-free conditions. We also show that the combination of two clinically approved medications that together activate Wnt–β-catenin and inhibit mTOR signaling increases the number (but not the proportion) of long-term HSCs in vivo.

Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.