Valproic acid (VPA) and lithium chloride (LiCl) are two primary mood-stabilizing drugs to exert neuroprotective effects and to treat bipolar disorder in clinic. Fibroblast growth factor 1 (FGF1) has been shown to regulate cell proliferation, cell division and neurogenesis. Human FGF1 gene 1B promoter ( -540 to+ 31)-driven green fluorescence (F1BGFP) has been shown to recapitulate endogenous FGF1 gene expression. It could also be used to isolate neural stem/progenitor cells (NSPCs) from developing and adult mouse brains as well as human brain tissues. We have previously shown that transcription factors RFX1, RFX2 and RFX3 could directly bind the 18-bp cis-element ( 484 to 467), and contribute to the maintenance of F1BGFP( + ) NSPCs. In this study, we provide several lines of evidence to demonstrate the underlying mechanisms of VPA and LiCl in activating FGF-1B promoter activity: (i) VPA and LiCl significantly up-regulated the F1BGFP expression; (ii) the induction of F1BGFP expression involves changes of RFX1-3 transcriptional complexes on the 18-bp cis-element of FGF-1B promoter; (iii) VPA and LiCl significantly increased the expression levels of FGF-1B, RFX2 and RFX3 transcripts; (iv) treatments of other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with GSK-3 siRNAs also activated FGF-1B promoter; (v) VPA specifically enhanced neuronal differentiation in F1BGFP( + ) NSPCs rather than GFP(-) cells. This study suggested, for the first time, that FGF1 is an important target for the mood stabilizers, VPA and LiCl. Our results provide valuable implications of VPA and LiCl in the treatment of bipolar disorder.
