|The mGluR Theory: Small Molecule Screen using Fragile X Neural Stem Cells
by Xuekun Li and Peng Jin, 4/30/2010
Neurogenesis, or the generation of new neurons, persists at a low level throughout life in two germinal zones of the brain, the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles Although the specific purpose of adult neurogenesis is not fully clear, mounting evidence points to its potentially important roles in adult neuroplasticity. The cellular basis of adult neurogenesis is neural stem/progenitor cells (NSPCs) residing in the two germinal zones. Our previous studies have shown that the loss of Fmrp led to increased proliferation and altered fate specification of aNSPCs both in vitro and in vivo. Fmrp-deficient aNSPCs displayed increased proliferation and decreased neuronal differentiation, but increased glial differentiation. These data unveil a novel regulatory role of Fmrp in adult neurogenesis and suggest that the altered adult neurogenesis in the absence of Fmrp could contribute to the pathogenesis of fragile X syndrome.
We have now established high throughput screening system using lentivirus expressing NeuroD1 promoter-luciferase reporter in cultured primary NSPCs. Through screening ~2,400 small molecules, we have identified several small molecules that could rescue the phenotype of Fmr1 KO aNSPCs. We are in the process of validating these small molecules in different systems, and continuing to screen additional small molecule libraries. The identification of these small molecules should provide additional therapeutic approaches for the treatment of fragile X syndrome.