Early metformin treatment: An effective approach for targeting fragile X syndrome pathophysiology

Abstract

Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder engendered by transcriptional silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Given the early onset of behavioral and molecular changes, it is imperative to know the optimal timing for therapeutic intervention. Case reports documented benefits of metformin treatment in FXS children between 2 and 14 y old. In this study, we administered metformin from birth to Fmr1^-/y mice which corrected up-regulated mitogen-2 activated protein kinase/extracellular signal-regulated kinase and mammalian/mechanistic target of rapamycin complex 1 signaling pathways and specific synaptic mRNA-binding targets of FMRP. Metformin rescued increased number of calls in ultrasonic vocalization and repetitive behavior in Fmr1^-/y mice. Our findings demonstrate that in mice, early-in-life metformin intervention is effective in treating FXS pathophysiology.

Keywords: Fmr1 KO mouse model; autism spectrum disorder; fragile X syndrome; mTORC1 and ERK signaling pathways; metformin.

Fig. 1.

Metformin from birth reduced up-regulated ERK and mTORC1 signaling. Representative immunoblots from vehicle and metformin-treated WT and Fmr1^−/y mice of phosphorylated and total levels of MEK (A and B), ERK (C and D), eIF4E (E and F), MMP-9 (G and H) and S6 (I and J) in HIP and PFC. Representative immunoblots from vehicle and metformin-treated WT and Fmr1^−/y mice of phosphorylated and total levels of ERK (K) and S6 (L) in the striatum. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as loading control.

Fig. 2.

Correction of synaptic FMRP-binding target levels and behavioral deficits. Representative immunoblots of MAP2 (A), eEF2 (B), PUM2 (C), and synapsin (D) in HIP of vehicle and metformin-treated WT and Fmr1^−/y mice. USV was measured as number of calls per minute (E) and call length (F). Repetitive behavior was assessed by measuring the time spent grooming (G) and the number of grooming bouts (H).