While Fragile X syndrome (FXS) is more common and often more severe in males, females with Fragile X can also experience significant challenges — including sensory sensitivities, anxiety, and seizures. This project aims to understand why Fragile X syndrome affects males and females differently, with a focus on how estrogen receptors in the brain may play a key role.

Most research to date has focused on males, so we know far less about how the disorder impacts females. Dr. Kimberly Huber’s team is working to close this gap. Their earlier studies suggest that a specific estrogen receptor, ERα (estrogen receptor alpha), may be involved in the brain circuit dysfunctions that lead to sensory processing problems and seizures in Fragile X syndrome.

With this new FRAXA award, the team will investigate how ERα affects neuron excitability — and whether blocking this receptor can help normalize brain activity. The goal is to lay the groundwork for sex-specific treatments for Fragile X.

To do this, they’ll compare male and female Fragile X mouse models, using advanced brain imaging and EEG-like recordings to track changes in brain activity. They’re also testing existing approved ERα-blocking drugs, originally developed for hormone-sensitive cancers, to see if these compounds can improve brain function and reduce audiogenic seizures — a key marker of brain hyperexcitability in Fragile X.