24h Quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice
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 def...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-06-01
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| Series: | Frontiers in Systems Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnsys.2014.00118/full |
| _version_ | 1811292021222014976 |
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| author | Michael V Johnston Simon eAmmanuel Cliona eODriscoll Amy eWozniak Sakkubai eNaidu Shilpa Dattatray Kadam |
| author_facet | Michael V Johnston Simon eAmmanuel Cliona eODriscoll Amy eWozniak Sakkubai eNaidu Shilpa Dattatray Kadam |
| author_sort | Michael V Johnston |
| collection | DOAJ |
| description | 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 24h 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 was 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. |
| first_indexed | 2024-04-13T04:39:07Z |
| format | Article |
| id | doaj.art-d177d492248842d3ad955ecc1a68b48c |
| institution | Directory Open Access Journal |
| issn | 1662-5137 |
| language | English |
| last_indexed | 2024-04-13T04:39:07Z |
| publishDate | 2014-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Systems Neuroscience |
| spelling | doaj.art-d177d492248842d3ad955ecc1a68b48c2022-12-22T03:02:05ZengFrontiers Media S.A.Frontiers in Systems Neuroscience1662-51372014-06-01810.3389/fnsys.2014.001189655724h Quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null miceMichael V Johnston0Simon eAmmanuel1Cliona eODriscoll2Amy eWozniak3Sakkubai eNaidu4Shilpa Dattatray Kadam5Kennedy Krieger Institute and Johns Hopkins University School of MedicineKennedy Krieger InstituteKennedy Krieger InstituteJohns Hopkins Public School of HealthKennedy Krieger Institute and Johns Hopkins University School of MedicineKennedy Krieger Institute and Johns Hopkins University School of MedicineMutations 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 24h 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 was 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.http://journal.frontiersin.org/Journal/10.3389/fnsys.2014.00118/fullRett SyndromeGlutamateMeCP2biomarkersSleep structure |
| spellingShingle | Michael V Johnston Simon eAmmanuel Cliona eODriscoll Amy eWozniak Sakkubai eNaidu Shilpa Dattatray Kadam 24h Quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice Frontiers in Systems Neuroscience Rett Syndrome Glutamate MeCP2 biomarkers Sleep structure |
| title | 24h Quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice |
| title_full | 24h Quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice |
| title_fullStr | 24h Quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice |
| title_full_unstemmed | 24h Quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice |
| title_short | 24h Quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice |
| title_sort | 24h quantitative eeg and in vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in mecp2 null mice |
| topic | Rett Syndrome Glutamate MeCP2 biomarkers Sleep structure |
| url | http://journal.frontiersin.org/Journal/10.3389/fnsys.2014.00118/full |
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