平成20年業績 学位

Glucocorticoids and lithium reciprocally regulate the proliferation of adult dentate gyrus-derived neural precursor cells through GSK-3β and β-catenin/TCF pathway

朴 秀賢

Adult hippocampal neurogenesis is decreased in rodent models for stress-related disorders at least partly through an elevated level of glucocorticoids. On the other hand, the mood stabilizer lithium (Li) commonly used for treatment of them increases it. This effect is thought to be one of therapeutic action of Li, but the molecular mechanism has been poorly understood. Here we established the culture system of adult rat dentate gyrus-derived neural precursor cells (ADPs) and examined the effects of dexamethasone (DEX), an agonist of glucocorcicoids receptor, and Li on ADP's proliferation. ADP is possible to be type-2a cell, which corresponds to be the second stage in a model of four differentiation stages in adult hippocampal neural precursor cells. DEX decreased ADP's proliferation, but Li did not have any effect on it. However, Li recovered ADP's proliferation decreased by DEX. The recovery effect of Li was abolished by quercetin (Que), an inhibitor of β-catenin/TCF pathway. The intra-nuclear translocation of β-catenin and expression of cyclin D1 are reciprocally regulated by DEX and Li in a similar way of the proliferation. In addition, DEX increased the phosphorylation of Tyr²¹⁶, which renders glycogen synthase kinase-3β (GSK-3β) active, on it. These results suggest that GSK-3β and β-catenin/TCF pathway might play a pivotal role in the reciprocal effects between DEX and Li on ADP's proliferation and are new targets of therapeutic agents for stress-related disorders.