FMRP regulation of STAT3-MYC signaling is critical for adult hippocampal neurogenesis and cognitive flexibility.

Fragile X syndrome (FXS), the most common form of inherited intellectual disability, results from a loss of fragile X mental retardation protein (FMRP), an RNA-binding protein whose deficiency impacts many targeted mRNA and brain functions. However, how these FMRP targets contribute to the pathogenesis of FXS is not fully understood, and effective treatment is lacking. Here, we identify signal transducer and activator of transcription 3 (STAT3) as a target of FMRP in adult hippocampal neural stem cells (NSCs). FMRP regulates Stat3 mRNA stability and protein translation, and loss of FMRP results in elevated Stat3 mRNA and protein, leading to aberrant neurogenesis and impaired dendritic maturation in adult NSCs and developing neurons. Activation of Stat3 in adult mouse hippocampal NSCs impairs cognitive flexibility. We show that STAT3 phosphorylation specifically binds to MYC, which is essential for adult hippocampal neurogenesis. Both genetic reduction of STAT3 and pharmacological treatment with artesunate, the first-line drug for treating malaria worldwide, rescue neurogenic and cognitive deficits in FMRP-deficient mice. Our work reveals a potential regulatory role for FMRP and STAT3-MYC signaling pathway in adult neurogenesis and cognitive flexibility, and provides a potential novel therapeutic strategy for treating adult FXS patients.