Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule

Adult neurogenesis continues throughout life in the mammalian hippocampus and plays a crucial role in memory and mood regulation. There is a growing interest in finding ways to enhance neurogenesis and maintain these hippocampal functions. Previous studies on a synthetic small molecule, isoxazole 9 (Isx-9), demonstrated its potential to promote neuronal differentiation in vitro. However, its effects on neurogenesis in vivo and its impact on hippocampal function remained unclear. In this study, we demonstrate that Isx-9 stimulates neurogenesis in vivo, boosting the proliferation and differentiation of neuroblasts in the hippocampal subgranular zone (SGZ) and enhancing the dendritic growth of newly generated neurons in the dentate gyrus. Additionally, Isx-9 improves hippocampal function, as evidenced by enhanced memory performance in the Morris water maze. Importantly, these effects occur without significant increases in cellular or overall animal activity, nor in vascularization. Investigating the molecular mechanisms underlying Isx-9′s promotion of neurogenesis (using FACS and microarray analysis of SGZ stem and progenitor cells) revealed the involvement of the myocyte-enhancer family of proteins (Mef2). Transgenic-induced knockout of all brain-enriched Mef2 isoforms (Mef2a/c/d) specifically in neural stem cells and their descendants confirmed the necessity of Mef2 for Isx-9-induced hippocampal neurogenesis. Therefore, Isx-9 enhances hippocampal neurogenesis and memory in vivo, with its effects dependent on Mef2, unveiling a new intrinsic molecular pathway that regulates adult neurogenesis.