Mood stabilizing drugs increase neural stem cells in the adult brain by activating Notch signaling

Bipolar disorder has an overall prevalence of approximately 1% among the general population and remains a chronic psychiatric illness carrying substantial health care costs. Mood stabilizing drugs, lithium, valproic acid and carbamazepine are commonly used to treat for stabilizing mood and managing acute depressive and manic symptoms within the bipolar disorder. However, the molecular mechanisms underlying the therapeutic action of these drugs and the disorder itself are largely unknown. In the present study, he demonstrated that lithium increased the number of dividing cells in the adult subventricular zone and dentate gyrus, which subsequently enhanced neurogenesis in the dentate gyrus of the hippocampus. Furthermore, using the colony-forming neurosphere assay, he firstly demonstrated that all mood stabilizers enhance self-renewal capability of neural stem cells and expand stem cell pool in the adult brain, and revealed the molecular mechanism of mood stabilizing drugs. First, he demonstrated that administration of lithium to adult mice for 3 weeks resulted in increased number of dividing cells in subventricular zone of lateral ventricules and the dentate gyrus of hippocampus using two methods, BrdU incorporatin and colonyforming neurosphere assay. Furthemore, neural stem cell derived from lithium, valproic acid or carbamazepine treated mice dramatically activated its self-renewal capability, whereas maintained its multipotentiality. These data indicated that all three mood stabilizers have the effects on expansion of the neural stem cell pool in the adult brain. Next, using in vitro colony-forming neurosphere assay, he demonstrated that mood stabilizing drugs at therapeutically-relevant concentrations in the cerebrospinal fluid, enhanced the formation of primary neurosphere and the resultant primary neurospheres produced more secondary neurospheres, whereas high does of mood stabilizers decreased the number of primary neurospheres and attenuated self-renewal capability of neural stem cells. These data indicated that mood stabilizing drugs at therapeutically-relevant concentrations in the cerebrospinal fluid have ability enhance self-renewal capability of neural stem cells. Final and most importantly, he clarified the molecular mechanism of mood stabilizers. Many biochemical pathways have been implicated in the therapeutic actions of mood stabilizers drugs, including crucial roles for glycogen synthase kinase-3β inhibition or inositol depletion. Glycogen synthase kinase-3β inhibition, however, was not detected in neurospheres treated with therapeutic does of mood stabilizers.Inositol depletion was not the cause of the enhanced self-renewal capability of neural stem cells either, because exogenously added myo-inositol did not revert the effects of mood stabilizers on neural stem cells.On the other hand, treatment with all three mood stabilizers activated Notch signaling is known to play critical roles in the maintenance of neural stem cell pool in the adult brain. He provided evidence for Notch signaling activation in the neural stem cell by means of quantitative RT-PCR analysis of target gene expression in this signal pathway, immunoblotting for an active form of Notch receptor and in situ hybridization analysys of Hes1/5 expression; treatment with mood stabilizers increased an active form of Notch receptor and upregulated its target genes in neural stem/progenitor cells both in vivoand in vitro, whereas co-culture with γ-secretase inhibitor or the presence of mutation in the presenilin1gene canceled the effect of mood stabilizers. These findings suggest that a shared pharmacological effect of mood stabilizing drugs is to enhance neurogenesis in the adult brain by activating Notch signaling in neural stem cells. Moreover, our results may lead not only to the clarification of the pathogenesis of bipolar disorder that is a burden of the society, but also to the development of new strategy to treat bipolar disorder patients