Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.

Fragile X syndrome is the leading monogenic cause of ASD. Trinucleotide repeats in the FMR1 gene abolish FMRP protein expression, leading to hyperactivation of ERK and mTOR signaling, upstream of mRNA translation. Here we show that metformin, the most widely used anti-type 2 diabetes drug, rescues core phenotypes in Fmr1-/y mice and selectively normalizes Erk signaling, Eif4e phosphorylation and the expression of Mmp9. Thus, metformin is a potential FXS therapeutic. Dysregulated mRNA translation is linked to core pathologies diagnosed in the Fragile X neurodevelopmental Syndrome (FXS), such as social and behavior problems, developmental delays and learning disabilities 1,2. In the brains of FXS patients and knockout mice (Fmr1-/y ; X-linked Fmr1 deletion in male mice), loss of Fragile X mental retardation protein (FMRP) results in hyperactivation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and the extracellular signal-regulated kinase (ERK) signaling pathways 1,2. Consistent with increased ERK activity, eukaryotic initiation factor 4E (eIF4E) phosphorylation is elevated in the brain of FXS patients and Fmr1-/y mice, thereby promoting translation of the mRNA encoding for matrix metalloproteinase 9 (MMP-9), which is elevated in the brains of both FXS patients and the Fmr1-/y mice 1-5. In accordance with these findings, knockout of Mmp9 rescues the majority of phenotypes in Fmr1-/y mice. MMP-9 degrades components of the extracellular matrix, including proteins important for synaptic function and maturation, which are implicated in FXS and autism spectrum disorders (ASD). Recent observations indicate that metformin, a first-line therapy for type 2 diabetes, imparts numerous health benefits beyond its original therapeutic use, such as decreased cancer risk and improved cancer prognosis 6. Metformin inhibits the mitochondrial respiratory chain complex 1, leading to a decrease in cellular energy state and thus activation of the energy sensor AMP-activated protein kinase (AMPK) 6. Several AMPK-independent activities of metformin have also been reported 7,8. Since metformin suppresses translation by inhibiting

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