Alterations in electroencephalography signals in female fragile X syndrome mouse model on a C57BL/6J background.

Abstract

Fragile X Syndrome (FXS), the most common monogenic cause of autism spectrum disorder, exhibits sex differences in prevalence and phenotypic severity. Electroencephalography provides translational insights into its pathophysiology, yet prior research focuses predominantly on males. In C57BL/6J mice, male Fmr1 knockout models show increased absolute gamma power across developmental stages, while female phenotypes, particularly in juveniles, remain uncharacterized. This study addresses this gap by comparing juvenile female Fmr1 knockout and wild-type mice. Frontal-parietal differential electroencephalography was recorded in home cage, light-dark test, and open field test. Analyses included absolute/relative power, peak alpha frequency, theta-beta ratio, phase-amplitude coupling, amplitude-amplitude coupling, and multiscale entropy. Knockout mice exhibited reduced absolute theta, alpha, and beta power across all conditions. Relative power analysis revealed decreased alpha and increased gamma activity. Phase-amplitude coupling showed diminished alpha-gamma coordination, while amplitude-amplitude coupling displayed state-dependent alterations. Peak alpha frequency and theta-beta ratio were reduced or unchanged depending on condition. Signal complexity remained comparable between genotypes. Behaviorally, knockout mice demonstrated hyper-exploration in the open field test. No robust correlations emerged between electroencephalography power and behavior. Our results demonstrate that juvenile female Fmr1 KO mice on a B6 background exhibit EEG alterations highly consistent with those reported in FXS patients, particularly increased gamma and reduced alpha power. The increase in gamma activity represents a conserved biomarker of potential cortical hyperexcitability, while alpha power reductions and decreased peak alpha frequency implicate thalamocortical network involvement. Together, these findings highlight the translational value of this model for studying core circuit dysfunctions in FXS.