Glucocorticoids and lithium reciprocally regulate the proliferation of adult dentate gyrus-derived neural precursor cells through GSK-3beta and beta-catenin/TCF pathway.
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 their treatment increases it. This effect is thought to be one of the therapeutic actions 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 glucocorticoids receptor, and Li on ADP proliferation. It is possible for ADP to be a type 2a cell, which corresponds to the second stage in a model of four differentiation stages in adult hippocampal neural precursor cells. DEX decreased ADP proliferation, but Li did not have any effect on it. However, Li recovered ADP proliferation decreased by DEX. The recovery effect of Li was abolished by quercetin, an inhibitor of beta-catenin/TCF pathway. The intranuclear translocation of beta-catenin and expression of cyclin D1 are reciprocally regulated by DEX and Li in a way similar to proliferation. In addition, DEX increased the phosphorylation of Tyr(216), which renders glycogen synthase kinase-3beta (GSK-3beta) active on it. These results suggest that GSK-3beta and beta-catenin/TCF pathway might be important in the reciprocal effects between DEX and Li on ADP proliferation and are new targets of therapeutic agents for stress-related disorders.
Boku
Shuken
S
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan. shuboku@med.hokudai.ac.jp
Nakagawa
Shin
S
Masuda
Takahiro
T
Nishikawa
Hiroyuki
H
Kato
Akiko
A
Kitaichi
Yuji
Y
Inoue
Takeshi
T
Koyama
Tsukasa
T
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D053687:Adult Stem Cells / Q000187:drug effects; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D055495:Neurogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000187:drug effects / Q000378:metabolism*
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D008301:Maleimides; D051820:TCF Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1; D003907:Dexamethasone; D008094:Lithium; D011794:Quercetin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3