Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the FMR1 gene. Interaction between estrogen receptor (ER) and lipid raft caveolae is critical for the estrogen signaling. Here, we tested the hypothesis that impaired ER–caveolae coupling contributes to the mental retardation of FXS.

Fmr1 knockout (KO) mouse was used as the model of FXS. Multiple techniques were performed including primary neuronal culture, short hairpin RNA (shRNA) interference, Western blot, electrophysiological recording, RNA‐binding protein immunoprecipitation, reverse transcriptase polymerase chain reaction, and behavioral tests.

In this study, we report that GluA1 surface expression and phosphorylation induced by 17β‐estradiol (E2) were impaired in the Fmr1 KO neurons. The E2‐mediated facilitation of long‐term potentiation and fear memory was impaired in the anterior cingulate cortex of Fmr1 KO mice. The increased coupling of caveolin‐1 (CAV1) and the membrane estrogen receptor ERα under basal conditions contributed to the impairment of ER signaling in Fmr1 KO neurons. FMRP (fragile X mental retardation protein) interacted with CAV1 mRNA, and knockdown of CAV1 with shRNA rescued the synaptic GluA1 delivery, plasticity, and memory in Fmr1 KO mice.

This is the first demonstration that the coupling between ERα and lipid raft CAV1 is critical for membrane ER signaling in synaptic plasticity. Therefore, increased coupling of CAV1 and ERα may elucidate a critical abnormal mechanism of FXS. Ann Neurol 2015;77:618–636