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Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome / Antonis ASIMINAS in Molecular Autism, 13 (2022)
[article]
Titre : Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Antonis ASIMINAS, Auteur ; Sam A. BOOKER, Auteur ; Owen R. DANDO, Auteur ; Zrinko KOZIC, Auteur ; Daisy ARKELL, Auteur ; Felicity H. INKPEN, Auteur ; Anna SUMERA, Auteur ; Irem AKYEL, Auteur ; Peter C. KIND, Auteur ; Emma R. WOOD, Auteur Article en page(s) : 49 p. Langues : Anglais (eng) Mots-clés : Mice Rats Animals Fragile X Syndrome/genetics Intellectual Disability Autism Spectrum Disorder Mice, Knockout Hippocampus/metabolism Fragile X Mental Retardation Protein/genetics Disease Models, Animal Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1(-/y)). METHODS: We recorded from the CA1 in Fmr1(-/y) and WT littermates over six 10-min exploration sessions in a novel environment-three sessions per day (ITI 10Â min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1(-/y) rats, respectively. RESULTS: On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1(-/y) rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1(-/y) rats. These findings were consistent with increased excitability of Fmr1(-/y) CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1(-/y) rats. LIMITATIONS: It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1(-/y) rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability. CONCLUSIONS: In conclusion, we found that hippocampal place cells from Fmr1(-/y) rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00528-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491
in Molecular Autism > 13 (2022) . - 49 p.[article] Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome [Texte imprimé et/ou numérique] / Antonis ASIMINAS, Auteur ; Sam A. BOOKER, Auteur ; Owen R. DANDO, Auteur ; Zrinko KOZIC, Auteur ; Daisy ARKELL, Auteur ; Felicity H. INKPEN, Auteur ; Anna SUMERA, Auteur ; Irem AKYEL, Auteur ; Peter C. KIND, Auteur ; Emma R. WOOD, Auteur . - 49 p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 49 p.
Mots-clés : Mice Rats Animals Fragile X Syndrome/genetics Intellectual Disability Autism Spectrum Disorder Mice, Knockout Hippocampus/metabolism Fragile X Mental Retardation Protein/genetics Disease Models, Animal Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1(-/y)). METHODS: We recorded from the CA1 in Fmr1(-/y) and WT littermates over six 10-min exploration sessions in a novel environment-three sessions per day (ITI 10Â min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1(-/y) rats, respectively. RESULTS: On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1(-/y) rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1(-/y) rats. These findings were consistent with increased excitability of Fmr1(-/y) CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1(-/y) rats. LIMITATIONS: It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1(-/y) rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability. CONCLUSIONS: In conclusion, we found that hippocampal place cells from Fmr1(-/y) rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00528-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability / C. L. WILKINSON in Molecular Autism, 12 (2021)
[article]
Titre : Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability Type de document : Texte imprimé et/ou numérique Auteurs : C. L. WILKINSON, Auteur ; C. A. NELSON, Auteur Article en page(s) : 17 p. Langues : Anglais (eng) Mots-clés : Brain/physiopathology Child Child Language Child, Preschool Electroencephalography Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/genetics/physiopathology/psychology Humans Male Biomarker E:I ratio Fragile X Syndrome Gamma Language Outcome measures Index. décimale : PER Périodiques Résumé : BACKGROUND: The lack of robust and reliable clinical biomarkers in Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, has limited the successful translation of bench-to-bedside therapeutics. While numerous drugs have shown promise in reversing synaptic and behavioral phenotypes in mouse models of FXS, none have demonstrated clinical efficacy in humans. Electroencephalographic (EEG) measures have been identified as candidate biomarkers as EEG recordings of both adults with FXS and mouse models of FXS consistently exhibit alterations in resting state and task-related activity. However, the developmental timing of these EEG differences is not known as thus far EEG studies have not focused on young children with FXS. Further, understanding how EEG differences are associated with core symptoms of FXS is crucial to successful use of EEG as a biomarker, and may improve our understanding of the disorder. METHODS: Resting-state EEG was collected from FXS boys with full mutation of Fmr1 (2.5-7 years old, n?=?11) and compared with both age-matched (n?=?12) and cognitive-matched (n?=?12) typically developing boys. Power spectra (including aperiodic and periodic components) were compared using non-parametric cluster-based permutation testing. Associations between 30 and 50 Hz gamma power and cognitive, language, and behavioral measures were evaluated using Pearson correlation and linear regression with age as a covariate. RESULTS: FXS participants showed increased power in the beta/gamma range (~?25-50 Hz) across multiple brain regions. Both a reduction in the aperiodic (1/f) slope and increase in beta/gamma periodic activity contributed to the significant increase in high-frequency power. Increased gamma power, driven by the aperiodic component, was associated with better language ability in the FXS group. No association was observed between gamma power and parent report measures of behavioral challenges, sensory hypersensitivities, or adaptive behaviors. LIMITATIONS: The study sample size was small, although comparable to other human studies in rare-genetic disorders. Findings are also limited to males in the age range studied. CONCLUSIONS: Resting-state EEG measures from this study in young boys with FXS identified similar increases in gamma power previously reported in adults and mouse models. The observed positive association between resting state aperiodic gamma power and language development supports hypotheses that alterations in some EEG measures may reflect ongoing compensatory mechanisms. En ligne : http://dx.doi.org/10.1186/s13229-021-00425-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 17 p.[article] Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability [Texte imprimé et/ou numérique] / C. L. WILKINSON, Auteur ; C. A. NELSON, Auteur . - 17 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 17 p.
Mots-clés : Brain/physiopathology Child Child Language Child, Preschool Electroencephalography Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/genetics/physiopathology/psychology Humans Male Biomarker E:I ratio Fragile X Syndrome Gamma Language Outcome measures Index. décimale : PER Périodiques Résumé : BACKGROUND: The lack of robust and reliable clinical biomarkers in Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, has limited the successful translation of bench-to-bedside therapeutics. While numerous drugs have shown promise in reversing synaptic and behavioral phenotypes in mouse models of FXS, none have demonstrated clinical efficacy in humans. Electroencephalographic (EEG) measures have been identified as candidate biomarkers as EEG recordings of both adults with FXS and mouse models of FXS consistently exhibit alterations in resting state and task-related activity. However, the developmental timing of these EEG differences is not known as thus far EEG studies have not focused on young children with FXS. Further, understanding how EEG differences are associated with core symptoms of FXS is crucial to successful use of EEG as a biomarker, and may improve our understanding of the disorder. METHODS: Resting-state EEG was collected from FXS boys with full mutation of Fmr1 (2.5-7 years old, n?=?11) and compared with both age-matched (n?=?12) and cognitive-matched (n?=?12) typically developing boys. Power spectra (including aperiodic and periodic components) were compared using non-parametric cluster-based permutation testing. Associations between 30 and 50 Hz gamma power and cognitive, language, and behavioral measures were evaluated using Pearson correlation and linear regression with age as a covariate. RESULTS: FXS participants showed increased power in the beta/gamma range (~?25-50 Hz) across multiple brain regions. Both a reduction in the aperiodic (1/f) slope and increase in beta/gamma periodic activity contributed to the significant increase in high-frequency power. Increased gamma power, driven by the aperiodic component, was associated with better language ability in the FXS group. No association was observed between gamma power and parent report measures of behavioral challenges, sensory hypersensitivities, or adaptive behaviors. LIMITATIONS: The study sample size was small, although comparable to other human studies in rare-genetic disorders. Findings are also limited to males in the age range studied. CONCLUSIONS: Resting-state EEG measures from this study in young boys with FXS identified similar increases in gamma power previously reported in adults and mouse models. The observed positive association between resting state aperiodic gamma power and language development supports hypotheses that alterations in some EEG measures may reflect ongoing compensatory mechanisms. En ligne : http://dx.doi.org/10.1186/s13229-021-00425-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 Genetic Testing in Patients with Neurodevelopmental Disorders: Experience of 511 Patients at Cincinnati Children's Hospital Medical Center / Xiaoli DU in Journal of Autism and Developmental Disorders, 52-11 (November 2022)
[article]
Titre : Genetic Testing in Patients with Neurodevelopmental Disorders: Experience of 511 Patients at Cincinnati Children's Hospital Medical Center Type de document : Texte imprimé et/ou numérique Auteurs : Xiaoli DU, Auteur ; Jennifer Elaine GLASS, Auteur ; Stephanie BALOW, Auteur ; Lisa M. DYER, Auteur ; Pamela A. RATHBUN, Auteur ; Qiaoning GUAN, Auteur ; Jie LIU, Auteur ; Yaning WU, Auteur ; D. Brian DAWSON, Auteur ; Lauren WALTERS-SEN, Auteur ; Teresa A. SMOLAREK, Auteur ; Wenying ZHANG, Auteur Article en page(s) : p.4828-4842 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/diagnosis Child DNA Copy Number Variations Female Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/diagnosis/genetics Genetic Testing Hospitals Humans Male Mutation Neurodevelopmental Disorders/diagnosis/genetics Retrospective Studies Trinucleotide Repeat Expansion Autism spectrum disorder (ASD) Copy number variant (CNV) Fragile X Mecp2 Neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Our institution developed and continuously improved a Neurodevelopmental Reflex (NDR) algorithm to help physicians with genetic test ordering for neurodevelopmental disorders (NDDs). To assess its performance, we performed a retrospective study of 511 patients tested through NDR from 2018 to 2019. SNP Microarray identified pathogenic/likely pathogenic copy number variations in 27/511 cases (5.28%). Among the 484 patients tested for Fragile X FMR1 CGG repeats, a diagnosis (0.20%) was established for one male mosaic for a full mutation, a premutation, and a one-CGG allele. Within the 101 normocephalic female patients tested for MECP2, two patients were found to carry pathogenic variants (1.98%). This retrospective study suggested the NDR algorithm effectively established diagnoses for patients with NDDs with a yield of 5.87%. En ligne : http://dx.doi.org/10.1007/s10803-021-05337-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=489
in Journal of Autism and Developmental Disorders > 52-11 (November 2022) . - p.4828-4842[article] Genetic Testing in Patients with Neurodevelopmental Disorders: Experience of 511 Patients at Cincinnati Children's Hospital Medical Center [Texte imprimé et/ou numérique] / Xiaoli DU, Auteur ; Jennifer Elaine GLASS, Auteur ; Stephanie BALOW, Auteur ; Lisa M. DYER, Auteur ; Pamela A. RATHBUN, Auteur ; Qiaoning GUAN, Auteur ; Jie LIU, Auteur ; Yaning WU, Auteur ; D. Brian DAWSON, Auteur ; Lauren WALTERS-SEN, Auteur ; Teresa A. SMOLAREK, Auteur ; Wenying ZHANG, Auteur . - p.4828-4842.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 52-11 (November 2022) . - p.4828-4842
Mots-clés : Autism Spectrum Disorder/diagnosis Child DNA Copy Number Variations Female Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/diagnosis/genetics Genetic Testing Hospitals Humans Male Mutation Neurodevelopmental Disorders/diagnosis/genetics Retrospective Studies Trinucleotide Repeat Expansion Autism spectrum disorder (ASD) Copy number variant (CNV) Fragile X Mecp2 Neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Our institution developed and continuously improved a Neurodevelopmental Reflex (NDR) algorithm to help physicians with genetic test ordering for neurodevelopmental disorders (NDDs). To assess its performance, we performed a retrospective study of 511 patients tested through NDR from 2018 to 2019. SNP Microarray identified pathogenic/likely pathogenic copy number variations in 27/511 cases (5.28%). Among the 484 patients tested for Fragile X FMR1 CGG repeats, a diagnosis (0.20%) was established for one male mosaic for a full mutation, a premutation, and a one-CGG allele. Within the 101 normocephalic female patients tested for MECP2, two patients were found to carry pathogenic variants (1.98%). This retrospective study suggested the NDR algorithm effectively established diagnoses for patients with NDDs with a yield of 5.87%. En ligne : http://dx.doi.org/10.1007/s10803-021-05337-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=489 Maternal Pragmatic Language Difficulties in the FMR1 Premutation and the Broad Autism Phenotype: Associations with Individual and Family Outcomes / J. KLUSEK in Journal of Autism and Developmental Disorders, 52-2 (February 2022)
[article]
Titre : Maternal Pragmatic Language Difficulties in the FMR1 Premutation and the Broad Autism Phenotype: Associations with Individual and Family Outcomes Type de document : Texte imprimé et/ou numérique Auteurs : J. KLUSEK, Auteur ; A. J. THURMAN, Auteur ; Leonard ABBEDUTO, Auteur Article en page(s) : p.835-851 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics Depression Family Female Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/genetics Humans Language Loneliness Mothers Phenotype Autism spectrum disorder Fragile X premutation Fragile X syndrome Social communication Index. décimale : PER Périodiques Résumé : Broader phenotypes associated with genetic liability, including mild difficulties with pragmatic language skills, have been documented in mothers of children with autism spectrum disorder (ASD) and mothers of children with fragile X syndrome (FXS). This study investigated the relationship between pragmatic difficulties and indicators of maternal well-being and family functioning. Pragmatic difficulty was associated with loneliness in mothers of children with ASD or FXS, and with depression, decreased life satisfaction, and poorer family relationship quality in mothers of children with FXS only. Results inform subtle maternal pragmatic language difficulties as a risk factor that that may contribute to reduced health and well-being, informing tailored support services to better meet the unique needs of families of children with ASD or FXS. En ligne : http://dx.doi.org/10.1007/s10803-021-04980-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=455
in Journal of Autism and Developmental Disorders > 52-2 (February 2022) . - p.835-851[article] Maternal Pragmatic Language Difficulties in the FMR1 Premutation and the Broad Autism Phenotype: Associations with Individual and Family Outcomes [Texte imprimé et/ou numérique] / J. KLUSEK, Auteur ; A. J. THURMAN, Auteur ; Leonard ABBEDUTO, Auteur . - p.835-851.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 52-2 (February 2022) . - p.835-851
Mots-clés : Autism Spectrum Disorder/genetics Depression Family Female Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/genetics Humans Language Loneliness Mothers Phenotype Autism spectrum disorder Fragile X premutation Fragile X syndrome Social communication Index. décimale : PER Périodiques Résumé : Broader phenotypes associated with genetic liability, including mild difficulties with pragmatic language skills, have been documented in mothers of children with autism spectrum disorder (ASD) and mothers of children with fragile X syndrome (FXS). This study investigated the relationship between pragmatic difficulties and indicators of maternal well-being and family functioning. Pragmatic difficulty was associated with loneliness in mothers of children with ASD or FXS, and with depression, decreased life satisfaction, and poorer family relationship quality in mothers of children with FXS only. Results inform subtle maternal pragmatic language difficulties as a risk factor that that may contribute to reduced health and well-being, informing tailored support services to better meet the unique needs of families of children with ASD or FXS. En ligne : http://dx.doi.org/10.1007/s10803-021-04980-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=455