Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome / Vidya SARAVANAPANDIAN in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 54 p. Titre : Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome Type de document : texte imprimé Auteurs : Vidya SARAVANAPANDIAN, Auteur ; Divya NADKARNI, Auteur ; Sheng-Hsiou HSU, Auteur ; Shaun A. HUSSAIN, Auteur ; Kiran MASKI, Auteur ; Peyman GOLSHANI, Auteur ; Christopher S. COLWELL, Auteur ; Saravanavel BALASUBRAMANIAN, Auteur ; Amos DIXON, Auteur ; Daniel H. GESCHWIND, Auteur ; Shafali S. JESTE, Auteur Article en page(s) : 54 p. Langues : Anglais (eng) Mots-clés : Autism  Biomarkers  Dup15q syndrome  Eeg  Gabaar  Sleep  Slow wave sleep  Spindles  UBE3A  Hoffmann-La Roche Ltd. and Yamo Pharmaceuticals. All the other authors declare that  they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Sleep disturbances in autism spectrum disorder (ASD) represent a common and vexing comorbidity. Clinical heterogeneity amongst these warrants studies of the mechanisms associated with specific genetic etiologies. Duplications of 15q11.2-13.1 (Dup15q syndrome) are highly penetrant for neurodevelopmental disorders (NDDs) such as intellectual disability and ASD, as well as sleep disturbances. Genes in the 15q region, particularly UBE3A and a cluster of GABA(A) receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased beta band oscillations (12-30 Hz) that likely reflect aberrant GABAergic neurotransmission. Healthy sleep rhythms, necessary for robust cognitive development, are also highly dependent on GABAergic neurotransmission. We therefore hypothesized that sleep physiology would be abnormal in children with Dup15q syndrome. METHODS: To test the hypothesis that elevated beta oscillations persist in sleep in Dup15q syndrome and that NREM sleep rhythms would be disrupted, we computed: (1) beta power, (2) spindle density, and (3) percentage of slow-wave sleep (SWS) in overnight sleep EEG recordings from a cohort of children with Dup15q syndrome (n = 15) and compared them to age-matched neurotypical children (n = 12). RESULTS: Children with Dup15q syndrome showed abnormal sleep physiology with elevated beta power, reduced spindle density, and reduced or absent SWS compared to age-matched neurotypical controls. LIMITATIONS: This study relied on clinical EEG where sleep staging was not available. However, considering that clinical polysomnograms are challenging to collect in this population, the ability to quantify these biomarkers on clinical EEG-routinely ordered for epilepsy monitoring-opens the door for larger-scale studies. While comparable to other human studies in rare genetic disorders, a larger sample would allow for examination of the role of seizure severity, medications, and developmental age that may impact sleep physiology. CONCLUSIONS: We have identified three quantitative EEG biomarkers of sleep disruption in Dup15q syndrome, a genetic condition highly penetrant for ASD. Insights from this study not only promote a greater mechanistic understanding of the pathophysiology defining Dup15q syndrome, but also lay the foundation for studies that investigate the association between sleep and cognition. Abnormal sleep physiology may undermine healthy cognitive development and may serve as a quantifiable and modifiable target for behavioral and pharmacological interventions. En ligne : http://dx.doi.org/10.1186/s13229-021-00460-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome [texte imprimé] / Vidya SARAVANAPANDIAN, Auteur ; Divya NADKARNI, Auteur ; Sheng-Hsiou HSU, Auteur ; Shaun A. HUSSAIN, Auteur ; Kiran MASKI, Auteur ; Peyman GOLSHANI, Auteur ; Christopher S. COLWELL, Auteur ; Saravanavel BALASUBRAMANIAN, Auteur ; Amos DIXON, Auteur ; Daniel H. GESCHWIND, Auteur ; Shafali S. JESTE, Auteur . - 54 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 54 p. Mots-clés : Autism  Biomarkers  Dup15q syndrome  Eeg  Gabaar  Sleep  Slow wave sleep  Spindles  UBE3A  Hoffmann-La Roche Ltd. and Yamo Pharmaceuticals. All the other authors declare that  they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Sleep disturbances in autism spectrum disorder (ASD) represent a common and vexing comorbidity. Clinical heterogeneity amongst these warrants studies of the mechanisms associated with specific genetic etiologies. Duplications of 15q11.2-13.1 (Dup15q syndrome) are highly penetrant for neurodevelopmental disorders (NDDs) such as intellectual disability and ASD, as well as sleep disturbances. Genes in the 15q region, particularly UBE3A and a cluster of GABA(A) receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased beta band oscillations (12-30 Hz) that likely reflect aberrant GABAergic neurotransmission. Healthy sleep rhythms, necessary for robust cognitive development, are also highly dependent on GABAergic neurotransmission. We therefore hypothesized that sleep physiology would be abnormal in children with Dup15q syndrome. METHODS: To test the hypothesis that elevated beta oscillations persist in sleep in Dup15q syndrome and that NREM sleep rhythms would be disrupted, we computed: (1) beta power, (2) spindle density, and (3) percentage of slow-wave sleep (SWS) in overnight sleep EEG recordings from a cohort of children with Dup15q syndrome (n = 15) and compared them to age-matched neurotypical children (n = 12). RESULTS: Children with Dup15q syndrome showed abnormal sleep physiology with elevated beta power, reduced spindle density, and reduced or absent SWS compared to age-matched neurotypical controls. LIMITATIONS: This study relied on clinical EEG where sleep staging was not available. However, considering that clinical polysomnograms are challenging to collect in this population, the ability to quantify these biomarkers on clinical EEG-routinely ordered for epilepsy monitoring-opens the door for larger-scale studies. While comparable to other human studies in rare genetic disorders, a larger sample would allow for examination of the role of seizure severity, medications, and developmental age that may impact sleep physiology. CONCLUSIONS: We have identified three quantitative EEG biomarkers of sleep disruption in Dup15q syndrome, a genetic condition highly penetrant for ASD. Insights from this study not only promote a greater mechanistic understanding of the pathophysiology defining Dup15q syndrome, but also lay the foundation for studies that investigate the association between sleep and cognition. Abnormal sleep physiology may undermine healthy cognitive development and may serve as a quantifiable and modifiable target for behavioral and pharmacological interventions. En ligne : http://dx.doi.org/10.1186/s13229-021-00460-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Dim light at night disrupts the sleep-wake cycle and exacerbates abnormal EEG activity in Cntnap2 knockout mice: implications for autism spectrum disorders / Yumeng WANG in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) Titre : Dim light at night disrupts the sleep-wake cycle and exacerbates abnormal EEG activity in Cntnap2 knockout mice: implications for autism spectrum disorders Type de document : texte imprimé Auteurs : Yumeng WANG, Auteur ; Ketema N. PAUL, Auteur ; Gene D. BLOCK, Auteur ; Tom DEBOER, Auteur ; Christopher S. COLWELL, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Epilepsy is a common comorbidity in individuals with autism spectrum disorders (ASDs). Many patients with epilepsy as well as ASD experience disruptions in their sleep-wake cycle and daily fluctuations in symptom severity. Chronic exposure to light at nighttime can disrupt sleep and circadian rhythms. Contactin associated protein-like 2 knockout (Cntnap2 KO) mice, a model of ASD and epilepsy, exhibit sleep and circadian disturbances and abnormal events in the electroencephalogram (EEG). Here, we investigated how chronic dim light at night (DLaN) exposure affects sleep architecture, EEG power spectra, and abnormal EEG events in Cntnap2 KO and wildtype (WT) mice. En ligne : https://doi.org/10.1186/s13229-025-00689-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=584 [article] Dim light at night disrupts the sleep-wake cycle and exacerbates abnormal EEG activity in Cntnap2 knockout mice: implications for autism spectrum disorders [texte imprimé] / Yumeng WANG, Auteur ; Ketema N. PAUL, Auteur ; Gene D. BLOCK, Auteur ; Tom DEBOER, Auteur ; Christopher S. COLWELL, Auteur. Langues : Anglais (eng) in Molecular Autism > 16 (2025) Index. décimale : PER Périodiques Résumé : Epilepsy is a common comorbidity in individuals with autism spectrum disorders (ASDs). Many patients with epilepsy as well as ASD experience disruptions in their sleep-wake cycle and daily fluctuations in symptom severity. Chronic exposure to light at nighttime can disrupt sleep and circadian rhythms. Contactin associated protein-like 2 knockout (Cntnap2 KO) mice, a model of ASD and epilepsy, exhibit sleep and circadian disturbances and abnormal events in the electroencephalogram (EEG). Here, we investigated how chronic dim light at night (DLaN) exposure affects sleep architecture, EEG power spectra, and abnormal EEG events in Cntnap2 KO and wildtype (WT) mice. En ligne : https://doi.org/10.1186/s13229-025-00689-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=584

Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome / Vidya SARAVANAPANDIAN in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome Type de document : texte imprimé Auteurs : Vidya SARAVANAPANDIAN, Auteur ; Melika MADANI, Auteur ; India NICHOLS, Auteur ; Scott VINCENT, Auteur ; Mary DOVER, Auteur ; Dante DIKEMAN, Auteur ; Benjamin D. PHILPOT, Auteur ; Toru TAKUMI, Auteur ; Christopher S. COLWELL, Auteur ; Shafali JESTE, Auteur ; Ketema N. PAUL, Auteur ; Peyman GOLSHANI, Auteur Langues : Anglais (eng) Mots-clés : Animals  Mice  Chromosomes, Human, Pair 15/genetics  Electroencephalography  Disease Models, Animal  Male  Female  Sleep Wake Disorders/genetics/physiopathology  Sleep/physiology/genetics  Trisomy/physiopathology/genetics  Chromosome Aberrations  Intellectual Disability  Autism  Biomarkers  Dup15q syndrome  Eeg  Gaba  Neurodevelopmental disorders  Sleep  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABA(A)R) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABA(A)Rs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations. En ligne : https://dx.doi.org/10.1186/s11689-024-09556-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome [texte imprimé] / Vidya SARAVANAPANDIAN, Auteur ; Melika MADANI, Auteur ; India NICHOLS, Auteur ; Scott VINCENT, Auteur ; Mary DOVER, Auteur ; Dante DIKEMAN, Auteur ; Benjamin D. PHILPOT, Auteur ; Toru TAKUMI, Auteur ; Christopher S. COLWELL, Auteur ; Shafali JESTE, Auteur ; Ketema N. PAUL, Auteur ; Peyman GOLSHANI, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Animals  Mice  Chromosomes, Human, Pair 15/genetics  Electroencephalography  Disease Models, Animal  Male  Female  Sleep Wake Disorders/genetics/physiopathology  Sleep/physiology/genetics  Trisomy/physiopathology/genetics  Chromosome Aberrations  Intellectual Disability  Autism  Biomarkers  Dup15q syndrome  Eeg  Gaba  Neurodevelopmental disorders  Sleep  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABA(A)R) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABA(A)Rs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations. En ligne : https://dx.doi.org/10.1186/s11689-024-09556-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

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