Yokukansan promotes neural stem cell proliferation: Implication of nuclear receptor TLX expression change

Aggressiveness and impulsivity are major problems in clinics of psychiatric care and they can often cause trouble and impairment in social activities. Although the biological mechanisms of these symptoms are unclear, recent reports suggest they are associated with deficits of the formation and maintenance of brain neural networks, especially dysfunctions of neurogenesis. The orphan nuclear receptor TLX has been suggested to have a pivotal role in embryonic and adult neurogenesis and TLX knockout mice show abnormal aggressive/impulsive behaviors. Here we report that alteration of TLX expression can exert proliferation and differentiation change in cultured neural stem cells (NSCs). The specifi c reduction of TLX by TLX-siRNA reduced NSC proliferation but increased differentiation to neurons and glias. The same concentrations of TLX-siRNA did not affect the survival and migration of NSCs. To examine the possible involvement of NSC function change in the biological mechanism underlining these symptoms, we analyzed NSC function and TLX expression changes induced by the Japanese traditional herbal medicine, Yokukansan, which is reported to be useful in the clinical treatment for symptoms of agitation and aggressiveness especially in dementia. Using the same NSC culture system, we found that treatment of Yokukansan or fibroblast growth factor 2 (FGF-2) promoted NSC proliferation and specifically increased expression of TLX. These findings may suggest that Yokukansan promotes NSC proliferation possibly via remarkable increase of orphan nuclear receptor TLX and this TLX-dysfunction-induced NSC proliferation change may, at least in part, correlate with a regulatory mechanism of aggressive behavior in a treatment response of Yokukansan.