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

Abstract

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.

Lithium chloride improves the efficiency of induced pluripotent stem cell-derived neurospheres

“…In Li-treated neurospheres, however, despite the induced increases in sizes, the survival of the neurospheres was not hampered but enhanced, implying that Li may enhance the oxygenation of the neurosphere ' s core to help the survival of neural progenitors. The increased number of viable NSCs by Li has also been shown by findings from other researchers, as a result of enhanced oxygenation and survival of neural progenitors ( Higashi et al, 2008 ;Zhou et al, 2011 ;Yin et al, 2014 ). Indeed, the enhanced survival was also seen in our model, as quantifying the apoptotic cells in Li-treated neurospheres showed a significant reduction compared to untreated neurospheres.…”

Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress

“…However at the doses used in the current study FLX has additional mechanisms of action, including a primary action of inhibiting serotonin reuptake (Wong et al, 1974). Increased activation of serotonin receptors results in cAMP-induced downstream effects, includingspecific activation of MAP kinases Erk1/2 (Tiraboschi et al, 2004), Notch signalling (Higashi et al, 2008) and BDNF release (Nibuya et al, 1995). Thus, FLX may increase BDNF through both ALLO-mediated and serotinergic mechanisms.…”

Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-β Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3-Kinase (PI3K)/Akt/Wnt/β-Catenin Pathway

“…We found that ETH induced neurogenesis mainly due to increased NSC proliferation and neuronal differentiation. Several studies have previously suggested that multiple intricate cell signaling cascades, including PI3K⅐Akt (54 -57), Wnt⅐␤-catenin (58), and Notch (59), are involved in NSC proliferation, differentiation, and survival of (60). Herein, we demonstrated that ETH induces NSC proliferation and differentiation through recruitment of the PI3K/Akt/Wnt/␤-catenin signaling pathway.…”

“…Further, valproate has been shown to suppress the inhibitory effect of dexamethasone on the proliferation of adult DG-derived NPCs via the GSK-3␤ and ␤-catenin pathway (28). Mood-stabilizing drugs enhance the self-renewal capacity of mouse NSC in vitro and the NSC pool in the adult brain through the activation of Notch signaling (59). Similar to the action of various drugs reported in the above studies, we found that ETH also enhances NSC proliferation, neuronal differentiation, and survival in the hippocampal region.…”