Blocked Inhibitory Serine-Phosphorylation of Glycogen Synthase Kinase-3α/β Impairs In Vivo Neural Precursor Cell Proliferation

Background: Adult neurogenesis augments neuronal plasticity, and deficient neurogenesis might contribute to mood disorders and schizophrenia and impede treatment responses. Because these diseases might be associated with inadequately controlled glycogen synthase kinase-3 (GSK3), we tested whether blocked inhibitory serine-phosphorylation of GSK3 impairs neurogenesis. Methods: Neural precursor cell (NPC) proliferation was measured by dentate gyrus bromodeoxyuridine (BrdU) labeling in GSK3 alpha/beta(21A/21A/9A/9A) knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3 while it remains within the physiological range, because GSK3 is not overexpressed. Results: There was a drastic 40% impairment in neurogenesis in vivo in GSK3 knockin mice compared with wild-type mice. Impaired neurogenesis could be due to effects of GSK3 in NPCs or in surrounding cells that modulate NPCs. In vitro proliferation was equivalent for NPCs from GSK3 knockin and wild-type mice, suggesting an in vivo deficiency in GSK3 knockin mice of external support for NPC proliferation. Measurements of two neurotrophins that promote neurogenesis demonstrated less hippocampal vascular endothelial growth factor but not brain-derived growth factor in GSK3 knockin mice than wild-type mice, reinforcing the possibility that insufficient environmental support in GSK3 knockin mice might contribute to impaired neurogenesis. In vivo chronic co-administration of lithium and fluoxetine, which each increase inhibitory serine-phosphorylation of wild-type GSK3, increased NPC proliferation in wild-type but not GSK3 knockin mice. Conclusions: Blocked inhibitory control of GSK3 impaired neurogenesis and the capacity of therapeutic drugs to stimulate neurogenesis, likely through deficient environmental factors that support neurogenesis, which might contribute to psychiatric diseases and responses to therapeutic drugs.