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Auteur D. H. GESCHWIND |
Documents disponibles écrits par cet auteur (3)
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Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome / V. SARAVANAPANDIAN in Molecular Autism, 12 (2021)
[article]
Titre : Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome Type de document : Texte imprimé et/ou numérique Auteurs : V. SARAVANAPANDIAN, Auteur ; D. NADKARNI, Auteur ; S. H. HSU, Auteur ; S. A. HUSSAIN, Auteur ; K. MASKI, Auteur ; P. GOLSHANI, Auteur ; C. S. COLWELL, Auteur ; S. BALASUBRAMANIAN, Auteur ; A. DIXON, Auteur ; D. H. GESCHWIND, Auteur ; S. 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
in Molecular Autism > 12 (2021) . - 54 p.[article] Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome [Texte imprimé et/ou numérique] / V. SARAVANAPANDIAN, Auteur ; D. NADKARNI, Auteur ; S. H. HSU, Auteur ; S. A. HUSSAIN, Auteur ; K. MASKI, Auteur ; P. GOLSHANI, Auteur ; C. S. COLWELL, Auteur ; S. BALASUBRAMANIAN, Auteur ; A. DIXON, Auteur ; D. H. GESCHWIND, Auteur ; S. 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 CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes / C. FRICANO-KUGLER in Molecular Autism, 10 (2019)
[article]
Titre : CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes Type de document : Texte imprimé et/ou numérique Auteurs : C. FRICANO-KUGLER, Auteur ; A. GORDON, Auteur ; G. SHIN, Auteur ; K. GAO, Auteur ; J. NGUYEN, Auteur ; J. BERG, Auteur ; M. STARKS, Auteur ; D. H. GESCHWIND, Auteur Article en page(s) : 25p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder (ASD) Cyfip1 Dup15q Fear conditioning Mouse behavior Neurodevelopmental disorders RNA sequencing Index. décimale : PER Périodiques Résumé : Background: CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 overexpression, as is observed in patients with CYFIP1 duplication, are less well understood. Methods: We developed and validated a mouse model of human CYFIP1 overexpression (CYFIP1 OE) using qPCR and western blot analysis. We performed a large battery of behavior testing on these mice, including ultrasonic vocalizations, three-chamber social assay, home-cage behavior, Y-maze, elevated plus maze, open field test, Morris water maze, fear conditioning, prepulse inhibition, and the hot plate assay. We also performed RNA sequencing and analysis on the basolateral amygdala. Results: Extensive behavioral testing in CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes, and myelination. We also identified GABA-A subunit composition changes in basolateral amygdala neurons, which are essential components of the neural fear conditioning circuit. Conclusion: Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1. En ligne : http://dx.doi.org/10.1186/s13229-019-0278-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402
in Molecular Autism > 10 (2019) . - 25p.[article] CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes [Texte imprimé et/ou numérique] / C. FRICANO-KUGLER, Auteur ; A. GORDON, Auteur ; G. SHIN, Auteur ; K. GAO, Auteur ; J. NGUYEN, Auteur ; J. BERG, Auteur ; M. STARKS, Auteur ; D. H. GESCHWIND, Auteur . - 25p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 25p.
Mots-clés : Autism spectrum disorder (ASD) Cyfip1 Dup15q Fear conditioning Mouse behavior Neurodevelopmental disorders RNA sequencing Index. décimale : PER Périodiques Résumé : Background: CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 overexpression, as is observed in patients with CYFIP1 duplication, are less well understood. Methods: We developed and validated a mouse model of human CYFIP1 overexpression (CYFIP1 OE) using qPCR and western blot analysis. We performed a large battery of behavior testing on these mice, including ultrasonic vocalizations, three-chamber social assay, home-cage behavior, Y-maze, elevated plus maze, open field test, Morris water maze, fear conditioning, prepulse inhibition, and the hot plate assay. We also performed RNA sequencing and analysis on the basolateral amygdala. Results: Extensive behavioral testing in CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes, and myelination. We also identified GABA-A subunit composition changes in basolateral amygdala neurons, which are essential components of the neural fear conditioning circuit. Conclusion: Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1. En ligne : http://dx.doi.org/10.1186/s13229-019-0278-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402 Strong correlation of downregulated genes related to synaptic transmission and mitochondria in post-mortem autism cerebral cortex / M. SCHWEDE in Journal of Neurodevelopmental Disorders, 10-1 (December 2018)
[article]
Titre : Strong correlation of downregulated genes related to synaptic transmission and mitochondria in post-mortem autism cerebral cortex Type de document : Texte imprimé et/ou numérique Auteurs : M. SCHWEDE, Auteur ; S. NAGPAL, Auteur ; M. J. GANDAL, Auteur ; N. N. PARIKSHAK, Auteur ; K. MIRNICS, Auteur ; D. H. GESCHWIND, Auteur ; E. M. MORROW, Auteur Année de publication : 2018 Article en page(s) : 18 p. Langues : Anglais (eng) Mots-clés : Autism Cortex Human Post-mortem Transcriptome Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic studies in autism have pinpointed a heterogeneous group of loci and genes. Further, environment may be an additional factor conferring susceptibility to autism. Transcriptome studies investigate quantitative differences in gene expression between patient-derived tissues and control. These studies may pinpoint genes relevant to pathophysiology yet circumvent the need to understand genetic architecture or gene-by-environment interactions leading to disease. METHODS: We conducted alternate gene set enrichment analyses using differentially expressed genes from a previously published RNA-seq study of post-mortem autism cerebral cortex. We used three previously published microarray datasets for validation and one of the microarray datasets for additional differential expression analysis. The RNA-seq study used 26 autism and 33 control brains in differential gene expression analysis, and the largest microarray dataset contained 15 autism and 16 control post-mortem brains. RESULTS: While performing a gene set enrichment analysis of genes differentially expressed in the RNA-seq study, we discovered that genes associated with mitochondrial function were downregulated in autism cerebral cortex, as compared to control. These genes were correlated with genes related to synaptic function. We validated these findings across the multiple microarray datasets. We also did separate differential expression and gene set enrichment analyses to confirm the importance of the mitochondrial pathway among downregulated genes in post-mortem autism cerebral cortex. CONCLUSIONS: We found that genes related to mitochondrial function were differentially expressed in autism cerebral cortex and correlated with genes related to synaptic transmission. Our principal findings replicate across all datasets investigated. Further, these findings may potentially replicate in other diseases, such as in schizophrenia. En ligne : http://dx.doi.org/10.1186/s11689-018-9237-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386
in Journal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 18 p.[article] Strong correlation of downregulated genes related to synaptic transmission and mitochondria in post-mortem autism cerebral cortex [Texte imprimé et/ou numérique] / M. SCHWEDE, Auteur ; S. NAGPAL, Auteur ; M. J. GANDAL, Auteur ; N. N. PARIKSHAK, Auteur ; K. MIRNICS, Auteur ; D. H. GESCHWIND, Auteur ; E. M. MORROW, Auteur . - 2018 . - 18 p.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 18 p.
Mots-clés : Autism Cortex Human Post-mortem Transcriptome Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic studies in autism have pinpointed a heterogeneous group of loci and genes. Further, environment may be an additional factor conferring susceptibility to autism. Transcriptome studies investigate quantitative differences in gene expression between patient-derived tissues and control. These studies may pinpoint genes relevant to pathophysiology yet circumvent the need to understand genetic architecture or gene-by-environment interactions leading to disease. METHODS: We conducted alternate gene set enrichment analyses using differentially expressed genes from a previously published RNA-seq study of post-mortem autism cerebral cortex. We used three previously published microarray datasets for validation and one of the microarray datasets for additional differential expression analysis. The RNA-seq study used 26 autism and 33 control brains in differential gene expression analysis, and the largest microarray dataset contained 15 autism and 16 control post-mortem brains. RESULTS: While performing a gene set enrichment analysis of genes differentially expressed in the RNA-seq study, we discovered that genes associated with mitochondrial function were downregulated in autism cerebral cortex, as compared to control. These genes were correlated with genes related to synaptic function. We validated these findings across the multiple microarray datasets. We also did separate differential expression and gene set enrichment analyses to confirm the importance of the mitochondrial pathway among downregulated genes in post-mortem autism cerebral cortex. CONCLUSIONS: We found that genes related to mitochondrial function were differentially expressed in autism cerebral cortex and correlated with genes related to synaptic transmission. Our principal findings replicate across all datasets investigated. Further, these findings may potentially replicate in other diseases, such as in schizophrenia. En ligne : http://dx.doi.org/10.1186/s11689-018-9237-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386