Assessment of the excitation–inhibition ratio in the Fmr1 KO2 mouse using neuronal oscillation dynamics

Abstract

In vitro and ex vivo studies have shown consistent indications of hyperexcitability in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mouse model of autism spectrum disorder. We recently introduced a method to quantify network–level functional excitation–inhibition ratio from the neuronal oscillations. Here, we used this measure to study whether the implicated synaptic excitation–inhibition disturbances translate to disturbances in network physiology in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) gene knockout model. Vigilance-state scoring was used to extract segments of inactive wakefulness as an equivalent behavioral condition to the human resting-state and, subsequently, we performed high-frequency resolution analysis of the functional excitation–inhibition biomarker, long-range temporal correlations, and spectral power. We corroborated earlier studies showing increased high-frequency power in Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mice. Long-range temporal correlations were higher in the gamma frequency ranges. Contrary to expectations, functional excitation–inhibition was lower in the knockout mice in high frequency ranges, suggesting more inhibition-dominated networks. Exposure to the Gamma-aminobutyric acid (GABA)-agonist clonazepam decreased the functional excitation–inhibition in both genotypes, confirming that increasing inhibitory tone results in a reduction of functional excitation–inhibition. In addition, clonazepam decreased electroencephalogram power and increased long-range temporal correlations in both genotypes. These findings show applicability of these new resting–state electroencephalogram biomarkers to animal for translational studies and allow investigation of the effects of lower-level disturbances in excitation–inhibition balance.

Adult Inception of Ketogenic Diet Therapy Increases Sleep during the Dark Cycle in C57BL/6J Wild Type and Fragile X Mice

“…There have been numerous recent studies, in human and rodent models of FXS, identifying EEG biomarkers [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. To our knowledge, our study was the first published work conducting 24 h polysomnography recordings in Fmr1 KO mice [ 43 ].…”