Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder / Laura SIMÕES DE OLIVEIRA in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 28p. Titre : Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder Type de document : texte imprimé Auteurs : Laura SIMÕES DE OLIVEIRA, Auteur ; Heather E. O'LEARY, Auteur ; Sarfaraz NAWAZ, Auteur ; Rita LOUREIRO, Auteur ; Elizabeth C. DAVENPORT, Auteur ; Paul S. BAXTER, Auteur ; Susana R LOUROS, Auteur ; Owen R. DANDO, Auteur ; Emma PERKINS, Auteur ; Julien PELTIER, Auteur ; Matthias TROST, Auteur ; Emily K. OSTERWEIL, Auteur ; Giles E. HARDINGHAM, Auteur ; Michael A. COUSIN, Auteur ; Sumantra CHATTARJI, Auteur ; Sam A. BOOKER, Auteur ; Timothy A. BENKE, Auteur ; David J. A. WYLLIE, Auteur ; Peter C. KIND, Auteur Article en page(s) : 28p. Langues : Anglais (eng) Mots-clés : Animals  Male  Rats  CA1 Region, Hippocampal/metabolism/pathology/physiopathology  Disease Models, Animal  Epileptic Syndromes/genetics/metabolism  Excitatory Postsynaptic Potentials  Genetic Diseases, X-Linked/genetics/metabolism/physiopathology  Hippocampus/metabolism  Long-Term Potentiation  Protein Serine-Threonine Kinases/metabolism/genetics  Pyramidal Cells/metabolism/pathology  Receptors, AMPA/metabolism/genetics  Receptors, N-Methyl-D-Aspartate/metabolism/genetics  Spasms, Infantile/genetics/metabolism  Synapses/metabolism  AMPA receptor  Cdkl5  NMDA receptor  hippocampus  intrinsic properties  rat  synaptic plasticity Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5(-/y) rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5(-/y) rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5(-/y) rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca(2+) permeable AMPA receptor mediated currents are unchanged in Cdkl5(-/y) rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD. En ligne : https://dx.doi.org/10.1186/s13229-024-00601-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder [texte imprimé] / Laura SIMÕES DE OLIVEIRA, Auteur ; Heather E. O'LEARY, Auteur ; Sarfaraz NAWAZ, Auteur ; Rita LOUREIRO, Auteur ; Elizabeth C. DAVENPORT, Auteur ; Paul S. BAXTER, Auteur ; Susana R LOUROS, Auteur ; Owen R. DANDO, Auteur ; Emma PERKINS, Auteur ; Julien PELTIER, Auteur ; Matthias TROST, Auteur ; Emily K. OSTERWEIL, Auteur ; Giles E. HARDINGHAM, Auteur ; Michael A. COUSIN, Auteur ; Sumantra CHATTARJI, Auteur ; Sam A. BOOKER, Auteur ; Timothy A. BENKE, Auteur ; David J. A. WYLLIE, Auteur ; Peter C. KIND, Auteur . - 28p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 28p. Mots-clés : Animals  Male  Rats  CA1 Region, Hippocampal/metabolism/pathology/physiopathology  Disease Models, Animal  Epileptic Syndromes/genetics/metabolism  Excitatory Postsynaptic Potentials  Genetic Diseases, X-Linked/genetics/metabolism/physiopathology  Hippocampus/metabolism  Long-Term Potentiation  Protein Serine-Threonine Kinases/metabolism/genetics  Pyramidal Cells/metabolism/pathology  Receptors, AMPA/metabolism/genetics  Receptors, N-Methyl-D-Aspartate/metabolism/genetics  Spasms, Infantile/genetics/metabolism  Synapses/metabolism  AMPA receptor  Cdkl5  NMDA receptor  hippocampus  intrinsic properties  rat  synaptic plasticity Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5(-/y) rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5(-/y) rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5(-/y) rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca(2+) permeable AMPA receptor mediated currents are unchanged in Cdkl5(-/y) rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD. En ligne : https://dx.doi.org/10.1186/s13229-024-00601-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS) / Melissa RASPA in Journal of Autism and Developmental Disorders, 55-3 (March 2025)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 55-3 (March 2025) . - p.997-1009 Titre : Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS) Type de document : texte imprimé Auteurs : Melissa RASPA, Auteur ; Angela GWALTNEY, Auteur ; Carla M. BANN, Auteur ; Jana VON HEHN, Auteur ; Timothy A. BENKE, Auteur ; Eric D. MARSH, Auteur ; Sarika U. PETERS, Auteur ; Amitha ANANTH, Auteur ; Alan K. PERCY, Auteur ; Jeffrey L. NEUL, Auteur Article en page(s) : p.997-1009 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Rett syndrome is a severe neurodevelopmental disorder that affects about 1 in 10,000 females. Clinical trials of disease modifying therapies are on the rise, but there are few psychometrically sound caregiver-reported outcome measures available to assess treatment benefit. We report on a new caregiver-reported outcome measure, the Rett Caregiver Assessment of Symptom Severity (RCASS). Using data from the Rett Natural History Study (n = 649), we examined the factor structure, using both exploratory and confirmatory factor analysis, and the reliability and validity of the RCASS. The four-factor model had the best overall fit, which covered movement, communication, behavior, and Rett-specific symptoms. The RCASS had moderate internal consistency. Strong face validity was found with age and mutation type, and convergent validity was established with other similar measures, including the Revised Motor-Behavior Assessment Scale, Clinical Severity Scale, Clinical Global Impression Scale, and the Child Health Questionnaire. These data provide initial evidence that the RCASS is a viable caregiver-outcome measure for use in clinical trials in Rett syndrome. Future work to assess sensitivity to change and other measures of reliability, such as test-retest and inter-rater agreement, are needed. En ligne : https://doi.org/10.1007/s10803-024-06238-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=548 [article] Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS) [texte imprimé] / Melissa RASPA, Auteur ; Angela GWALTNEY, Auteur ; Carla M. BANN, Auteur ; Jana VON HEHN, Auteur ; Timothy A. BENKE, Auteur ; Eric D. MARSH, Auteur ; Sarika U. PETERS, Auteur ; Amitha ANANTH, Auteur ; Alan K. PERCY, Auteur ; Jeffrey L. NEUL, Auteur . - p.997-1009. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 55-3 (March 2025) . - p.997-1009 Index. décimale : PER Périodiques Résumé : Rett syndrome is a severe neurodevelopmental disorder that affects about 1 in 10,000 females. Clinical trials of disease modifying therapies are on the rise, but there are few psychometrically sound caregiver-reported outcome measures available to assess treatment benefit. We report on a new caregiver-reported outcome measure, the Rett Caregiver Assessment of Symptom Severity (RCASS). Using data from the Rett Natural History Study (n = 649), we examined the factor structure, using both exploratory and confirmatory factor analysis, and the reliability and validity of the RCASS. The four-factor model had the best overall fit, which covered movement, communication, behavior, and Rett-specific symptoms. The RCASS had moderate internal consistency. Strong face validity was found with age and mutation type, and convergent validity was established with other similar measures, including the Revised Motor-Behavior Assessment Scale, Clinical Severity Scale, Clinical Global Impression Scale, and the Child Health Questionnaire. These data provide initial evidence that the RCASS is a viable caregiver-outcome measure for use in clinical trials in Rett syndrome. Future work to assess sensitivity to change and other measures of reliability, such as test-retest and inter-rater agreement, are needed. En ligne : https://doi.org/10.1007/s10803-024-06238-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=548

Validating the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC) Beyond Infancy in the CDKL5 Deficiency Disorder / Helen LEONARD ; Kingsley WONG ; Peter JACOBY ; Mary SPENCE ; Eric D. MARSH ; Timothy A. BENKE ; Scott DEMAREST ; Jenny DOWNS in Journal of Autism and Developmental Disorders, 54-7 (July 2024)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 54-7 (July 2024) . - p.2526-2535 Titre : Validating the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC) Beyond Infancy in the CDKL5 Deficiency Disorder Type de document : texte imprimé Auteurs : Helen LEONARD, Auteur ; Kingsley WONG, Auteur ; Peter JACOBY, Auteur ; Mary SPENCE, Auteur ; Eric D. MARSH, Auteur ; Timothy A. BENKE, Auteur ; Scott DEMAREST, Auteur ; Jenny DOWNS, Auteur Article en page(s) : p.2526-2535 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : CDKL5 deficiency disorder (CDD) results in early-onset epilepsy and lifelong cognitive and motor impairments. With no validated measure for communication in CDD, this study evaluated the psychometric properties of the Communication and Symbolic Behavior Scales-Developmental Profile Infant Toddler Checklist (CSBS-DP ITC). Caregivers (n = 150; affected individuals aged 1-29 years) completed the CSBS-DP ITC. Distribution of scores indicated a floor effect. There was poor divergent validity for the three-factor model but goodness of fit and convergent validity data were satisfactory for the one-factor model. Individuals with poorer overall functional abilities scored lower on the CSBS-DP ITC. Test-retest reliability was excellent. The floor effect could explain the very high reliability, suggesting problems as a sensitive outcome measure in clinical trials for CDD. En ligne : https://doi.org/10.1007/s10803-023-06002-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=533 [article] Validating the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC) Beyond Infancy in the CDKL5 Deficiency Disorder [texte imprimé] / Helen LEONARD, Auteur ; Kingsley WONG, Auteur ; Peter JACOBY, Auteur ; Mary SPENCE, Auteur ; Eric D. MARSH, Auteur ; Timothy A. BENKE, Auteur ; Scott DEMAREST, Auteur ; Jenny DOWNS, Auteur . - p.2526-2535. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 54-7 (July 2024) . - p.2526-2535 Index. décimale : PER Périodiques Résumé : CDKL5 deficiency disorder (CDD) results in early-onset epilepsy and lifelong cognitive and motor impairments. With no validated measure for communication in CDD, this study evaluated the psychometric properties of the Communication and Symbolic Behavior Scales-Developmental Profile Infant Toddler Checklist (CSBS-DP ITC). Caregivers (n = 150; affected individuals aged 1-29 years) completed the CSBS-DP ITC. Distribution of scores indicated a floor effect. There was poor divergent validity for the three-factor model but goodness of fit and convergent validity data were satisfactory for the one-factor model. Individuals with poorer overall functional abilities scored lower on the CSBS-DP ITC. Test-retest reliability was excellent. The floor effect could explain the very high reliability, suggesting problems as a sensitive outcome measure in clinical trials for CDD. En ligne : https://doi.org/10.1007/s10803-023-06002-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=533

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