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TISSUE-SPECIFIC STEM CELLS

Mood Stabilizing Drugs Expand the Neural Stem Cell Pool in the Adult Brain Through Activation of Notch Signaling

^aDepartment of Physiological Sciences, School of Life Sciences, Graduate University for Advanced Studies, Kanagawa, Japan;
^bDivision of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan;
^cDepartment of Psychiatry, Health Service Center, University of Tokyo, Tokyo, Japan;
^dSamuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

Key Words. Lithium • Valproic acid • Carbamazepine • Neural stem cell • Self-renewal • Notch

Correspondence: Seiji Hitoshi, M.D., Ph.D., Division of Neurobiology & Bioinformatics, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan. Telephone: +81-564-59-5246; Fax: +81-564-59-5247; e-mail: shitoshi-tky{at}umin.ac.jp

Received December 7, 2007; accepted for publication April 28, 2008.
First published online in STEM CELLS EXPRESS   May 8, 2008.

Neural stem cells (NSCs) have attracted considerable attention as a potential source of cells for therapeutic treatment of impaired areas of the central nervous system. However, efficient and clinically feasible strategies for expansion of the endogenous NSC pool are currently unavailable. In this study, we demonstrate that mood stabilizing drugs, which are used to treat patients with bipolar disorder, enhance the self-renewal capability of mouse NSCs in vitro and that this enhancement is achieved at therapeutically relevant concentrations in the cerebrospinal fluid. The pharmacological effects are mediated by the activation of Notch signaling in the NSC. Treatment with mood stabilizers increased an active form of Notch receptor and upregulated its target genes in neural stem/progenitor cells, whereas coculture with -secretase inhibitor or the presence of mutation in the presenilin1 gene blocked the effects of mood stabilizers. In addition, chronic administration of mood stabilizers expanded the NSC pool in the adult brain, which subsequently increased the cell supply to the olfactory bulb. We suggest that treatment with mood stabilizing drugs could be used to facilitate regeneration following insult to the central nervous system.

Disclosure of potential conflicts of interest is found at the end of this article.