Mutations in the X-linked gene encoding
methyl-CpG-binding protein 2 (Mecp2) cause most cases of
Rett syndrome (RTT). Currently there is no cure for RTT. Abnormal EEGs are found in 100% of RTT cases and are associated with severe sleep dysfunction, the cause of which is not well understood. Mice deficient in
MeCP2 protein have been studied and characterized for their neuropathological and behavioral deficits to better understand RTT. With the goal to study the non-ictal EEG correlates in symptomatic Mecp2 KO mice (Mecp2(tm1.1Bird/y)), and determine novel EEG
biomarkers of their reported progressive neurodegeneration, we used 24 h video-EEG/EMG with synchronous in-vivo cortical
glutamate biosensor in the frontal cortex. We scored the EEG for activity states and spectral analysis was performed to evaluate correlations to the synchronous extracellular
glutamate fluctuations underlying Mecp2 inactivation as compared to WT. Significant alterations in sleep structure due to dark cycle-specific long wake states and poor quality of slow-wave sleep were associated with a significant increase in
glutamate loads per activity cycle. The dynamics of the activity-state-dependent physiological rise and fall of
glutamate indicative of
glutamate homeostasis were significantly altered in the KO mice. Colorimetric quantitation of absolute
glutamate levels in frontal cortex also indicated the presence of significantly higher levels in KO. This study for the first time found evidence of uncompensated
sleep deprivation-like EEG
biomarkers that were associated with
glutamate homeostatic dysfunction in the Mecp2 KO mice.