Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice.

Michael V Johnston,Amy Wozniak,Cliona O'Driscoll,Simon Ammanuel,Sakkubai Naidu,Shilpa D Kadam

doi:10.3389/fnsys.2014.00118

Michael V Johnston, Amy Wozniak + Show 4 more

Open Access

https://doi.org/10.3389/fnsys.2014.00118

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Abstract

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 (Mecp2tm1.1Bird/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.

Highlights

Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder which is a common cause for genetic mental retardation in girls, one in every 8500 live births
24 h EEG/EMG recordings analyzed with confirmation from synchronous video recordings revealed significant sleep dysfunction in methyl-CpG-binding protein 2 (Mecp2) knock out (KO) mice compared to their age-matched wild-type mice (WT) littermates (Figure 1A)
Since all mice in the study were introduced into a novel tethered chamber for the recording period, and heightened anxiety behavior has been documented in Mecp2 null mice (Lang et al, 2014); the first wake cycle durations were analyzed and found to be longer in KO mice compared to WT (Figure 1C5), not significantly (p = 0.06)

Summary

Introduction

Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder which is a common cause for genetic mental retardation in girls, one in every 8500 live births. Mutations in the gene encoding Mecp (methyl-CpGbinding protein 2) are known to cause the majority of cases (90–95%, Neul et al, 2008) of typical RTT and are found in neuropsychiatric syndromes like autism, bipolar disorder with. Epilepsy is a major co-morbidity [60–80%, abnormal EEGs are found in 100% of RTT cases (Glaze et al, 1998; Hagberg, 2002; Moser et al, 2007; Glaze et al, 2010; Pintaudi et al, 2010)]. Little is known about the mechanisms by which chronic sleep dysfunction modulates the severity of temporal deterioration in the regression stage in RTT. Video-EEG monitoring has been suggested to provide definitive information regarding the need for therapy in RTT (Glaze et al, 1998)

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