Better statistical reporting does not lead to statistical rigour: lessons from two decades of pseudoreplication in mouse-model studies of neurological disorders / Constantinos ELEFTHERIOU in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 30 Titre : Better statistical reporting does not lead to statistical rigour: lessons from two decades of pseudoreplication in mouse-model studies of neurological disorders Type de document : texte imprimé Auteurs : Constantinos ELEFTHERIOU, Auteur ; Sarah GIACHETTI, Auteur ; Raven HICKSON, Auteur ; Laura KAMNIOTI-DUMONT, Auteur ; Robert TEMPLAAR, Auteur ; Alina AALTONEN, Auteur ; Eleni TSOUKALA, Auteur ; Nawon KIM, Auteur ; Lysandra FRYER-PETRIDIS, Auteur ; Chloe HENLEY, Auteur ; Ceren ERDEM, Auteur ; Emma WILSON, Auteur ; Beatriz MAIO, Auteur ; Jingjing YE, Auteur ; Jessica C. PIERCE, Auteur ; Kath MAZUR, Auteur ; Lucia LANDA-NAVARRO, Auteur ; Nina G. PETROVIĆ, Auteur ; Sarah BENDOVA, Auteur ; Hanan WOODS, Auteur ; Manuela RIZZI, Auteur ; Vanesa SALAZAR-SANCHEZ, Auteur ; Natasha J. ANSTEY, Auteur ; Antonios ASIMINAS, Auteur ; Shinjini BASU, Auteur ; Sam A. BOOKER, Auteur ; Anjanette HARRIS, Auteur ; Sam HEYES, Auteur ; Adam D. JACKSON, Auteur ; Alex CROCKER-BUQUE, Auteur ; Aoife C. MCMAHON, Auteur ; Sally M. TILL, Auteur ; Lasani S. WIJETUNGE, Auteur ; David J.A. WYLLIE, Auteur ; Catherine M. ABBOTT, Auteur ; Timothy O'LEARY, Auteur ; Peter C. KIND, Auteur ; Constantinos ELEFTHERIOU, Auteur ; Sarah GIACHETTI, Auteur ; Raven HICKSON, Auteur ; Laura KAMNIOTI-DUMONT, Auteur ; Robert TEMPLAAR, Auteur ; Alina AALTONEN, Auteur ; Eleni TSOUKALA, Auteur ; Nawon KIM, Auteur ; Lysandra FRYER-PETRIDIS, Auteur ; Chloe HENLEY, Auteur ; Ceren ERDEM, Auteur ; Emma WILSON, Auteur ; Beatriz MAIO, Auteur ; Jingjing YE, Auteur ; Jessica C. PIERCE, Auteur ; Kath MAZUR, Auteur ; Lucia LANDA-NAVARRO, Auteur ; Nina G. PETROVIĆ, Auteur ; Sarah BENDOVA, Auteur ; Hanan WOODS, Auteur ; Manuela RIZZI, Auteur ; Vanesa SALAZAR-SANCHEZ, Auteur ; Natasha J. ANSTEY, Auteur ; Antonios ASIMINAS, Auteur ; Shinjini BASU, Auteur ; Sam A. BOOKER, Auteur ; Anjanette HARRIS, Auteur ; Sam HEYES, Auteur ; Adam D. JACKSON, Auteur ; Alex CROCKER-BUQUE, Auteur ; Aoife C. MCMAHON, Auteur ; Sally M. TILL, Auteur ; Lasani S. WIJETUNGE, Auteur ; David J.A. WYLLIE, Auteur ; Catherine M. ABBOTT, Auteur ; Timothy O'LEARY, Auteur ; Peter C. KIND, Auteur Article en page(s) : 30 Langues : Anglais (eng) Mots-clés : Animals  Mice  Disease Models, Animal  Nervous System Diseases  Research Design  Animal models  Autism  Fragile X  Pseudoreplication  Statistics  for publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Accurately determining the sample size ("N") of a dataset is a key consideration for experimental design. Misidentification of sample size can lead to pseudoreplication, a process of artificially inflating the number of experimental replicates which systematically underestimates variability, overestimates effect sizes and invalidates statistical tests performed on the data. While many journals have adopted stringent requirements with regard to statistical reporting over the last decade, it remains unknown whether such efforts have had a meaningful impact on statistical rigour. METHODS: Here, we evaluated the prevalence of this type of statistical error among neuroscience studies involving animal models of Fragile-X Syndrome (FXS) and those using animal models of neurological disorders at large published between 2001 and 2024. RESULTS: We found that pseudoreplication was present in the majority of publication, increasing over time despite marked improvements in statistical reporting over the last decade. This trend generalised beyond the FXS literature to rodent studies of neurological disorders at large between 2012 and 2024, suggesting that pseudoreplication remains a widespread issue in the literature. LIMITATIONS: The scope of this study was limited to rodent-model studies of neurological disorders which had the potential for being pseudoreplicated, by allowing repeat observations from individual animals. We did not consider reviews or articles whose experimental design could not allow for pseudoreplication, for example studies which reported only behavioural results, or studies which did not use inferential statistics. CONCLUSIONS: These observations identify an urgent need for better standards in experimental design and increased vigilance for this type of error during peer review. While reporting standards have significantly improved over the past two decades, this alone has not been enough to curb the prevalence of pseudoreplication. We offer suggestions for how this can be remedied as well as quantifying the severity of this particular type of statistical error. Although the examined literature concerns a specific neuroscience-related area of research, the implications of pseudoreplication apply to all fields of empirical research. En ligne : https://dx.doi.org/10.1186/s13229-025-00663-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=569 [article] Better statistical reporting does not lead to statistical rigour: lessons from two decades of pseudoreplication in mouse-model studies of neurological disorders [texte imprimé] / Constantinos ELEFTHERIOU, Auteur ; Sarah GIACHETTI, Auteur ; Raven HICKSON, Auteur ; Laura KAMNIOTI-DUMONT, Auteur ; Robert TEMPLAAR, Auteur ; Alina AALTONEN, Auteur ; Eleni TSOUKALA, Auteur ; Nawon KIM, Auteur ; Lysandra FRYER-PETRIDIS, Auteur ; Chloe HENLEY, Auteur ; Ceren ERDEM, Auteur ; Emma WILSON, Auteur ; Beatriz MAIO, Auteur ; Jingjing YE, Auteur ; Jessica C. PIERCE, Auteur ; Kath MAZUR, Auteur ; Lucia LANDA-NAVARRO, Auteur ; Nina G. PETROVIĆ, Auteur ; Sarah BENDOVA, Auteur ; Hanan WOODS, Auteur ; Manuela RIZZI, Auteur ; Vanesa SALAZAR-SANCHEZ, Auteur ; Natasha J. ANSTEY, Auteur ; Antonios ASIMINAS, Auteur ; Shinjini BASU, Auteur ; Sam A. BOOKER, Auteur ; Anjanette HARRIS, Auteur ; Sam HEYES, Auteur ; Adam D. JACKSON, Auteur ; Alex CROCKER-BUQUE, Auteur ; Aoife C. MCMAHON, Auteur ; Sally M. TILL, Auteur ; Lasani S. WIJETUNGE, Auteur ; David J.A. WYLLIE, Auteur ; Catherine M. ABBOTT, Auteur ; Timothy O'LEARY, Auteur ; Peter C. KIND, Auteur ; Constantinos ELEFTHERIOU, Auteur ; Sarah GIACHETTI, Auteur ; Raven HICKSON, Auteur ; Laura KAMNIOTI-DUMONT, Auteur ; Robert TEMPLAAR, Auteur ; Alina AALTONEN, Auteur ; Eleni TSOUKALA, Auteur ; Nawon KIM, Auteur ; Lysandra FRYER-PETRIDIS, Auteur ; Chloe HENLEY, Auteur ; Ceren ERDEM, Auteur ; Emma WILSON, Auteur ; Beatriz MAIO, Auteur ; Jingjing YE, Auteur ; Jessica C. PIERCE, Auteur ; Kath MAZUR, Auteur ; Lucia LANDA-NAVARRO, Auteur ; Nina G. PETROVIĆ, Auteur ; Sarah BENDOVA, Auteur ; Hanan WOODS, Auteur ; Manuela RIZZI, Auteur ; Vanesa SALAZAR-SANCHEZ, Auteur ; Natasha J. ANSTEY, Auteur ; Antonios ASIMINAS, Auteur ; Shinjini BASU, Auteur ; Sam A. BOOKER, Auteur ; Anjanette HARRIS, Auteur ; Sam HEYES, Auteur ; Adam D. JACKSON, Auteur ; Alex CROCKER-BUQUE, Auteur ; Aoife C. MCMAHON, Auteur ; Sally M. TILL, Auteur ; Lasani S. WIJETUNGE, Auteur ; David J.A. WYLLIE, Auteur ; Catherine M. ABBOTT, Auteur ; Timothy O'LEARY, Auteur ; Peter C. KIND, Auteur . - 30. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 30 Mots-clés : Animals  Mice  Disease Models, Animal  Nervous System Diseases  Research Design  Animal models  Autism  Fragile X  Pseudoreplication  Statistics  for publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Accurately determining the sample size ("N") of a dataset is a key consideration for experimental design. Misidentification of sample size can lead to pseudoreplication, a process of artificially inflating the number of experimental replicates which systematically underestimates variability, overestimates effect sizes and invalidates statistical tests performed on the data. While many journals have adopted stringent requirements with regard to statistical reporting over the last decade, it remains unknown whether such efforts have had a meaningful impact on statistical rigour. METHODS: Here, we evaluated the prevalence of this type of statistical error among neuroscience studies involving animal models of Fragile-X Syndrome (FXS) and those using animal models of neurological disorders at large published between 2001 and 2024. RESULTS: We found that pseudoreplication was present in the majority of publication, increasing over time despite marked improvements in statistical reporting over the last decade. This trend generalised beyond the FXS literature to rodent studies of neurological disorders at large between 2012 and 2024, suggesting that pseudoreplication remains a widespread issue in the literature. LIMITATIONS: The scope of this study was limited to rodent-model studies of neurological disorders which had the potential for being pseudoreplicated, by allowing repeat observations from individual animals. We did not consider reviews or articles whose experimental design could not allow for pseudoreplication, for example studies which reported only behavioural results, or studies which did not use inferential statistics. CONCLUSIONS: These observations identify an urgent need for better standards in experimental design and increased vigilance for this type of error during peer review. While reporting standards have significantly improved over the past two decades, this alone has not been enough to curb the prevalence of pseudoreplication. We offer suggestions for how this can be remedied as well as quantifying the severity of this particular type of statistical error. Although the examined literature concerns a specific neuroscience-related area of research, the implications of pseudoreplication apply to all fields of empirical research. En ligne : https://dx.doi.org/10.1186/s13229-025-00663-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=569

Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder / Mohammed Sarfaraz NAWAZ ; Peter C. KIND ; Michael A. COUSIN in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 26 Titre : Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder Type de document : texte imprimé Auteurs : Mohammed Sarfaraz NAWAZ, Auteur ; Peter C. KIND, Auteur ; Michael A. COUSIN, Auteur Article en page(s) : 26 Langues : Anglais (eng) Mots-clés : Animals  Endocytosis  Disease Models, Animal  Rats  Synaptic Vesicles/metabolism  Autism Spectrum Disorder/metabolism/physiopathology/genetics/pathology  Neurons/metabolism  Cells, Cultured  Exocytosis  Activity  Autism  Hippocampus  Presynapse  Rat  Vesicle  performed in accordance with the UK Animal (Scientific Procedures) Act 1986,  under Project and Personal Licence authority and were approved by the Animal  Welfare and Ethical Review Body at the University of Edinburgh (Home Office  project licence - 7008878). Similarly, procedures were conducted in accordance  with protocols approved by the Institutional Animal Ethics Committee of Institute  for Stem Cell Science and Regenerative Medicine, Bangalore. Consent for  publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. Index. décimale : PER Périodiques Résumé : BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment. METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1(+/-), Nlgn3(-/y), Syngap(+/-), Syngap(+/?-GAP), Pten(+/-)) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran. RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis. LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression. CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons. En ligne : https://dx.doi.org/10.1186/s13229-025-00660-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder [texte imprimé] / Mohammed Sarfaraz NAWAZ, Auteur ; Peter C. KIND, Auteur ; Michael A. COUSIN, Auteur . - 26. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 26 Mots-clés : Animals  Endocytosis  Disease Models, Animal  Rats  Synaptic Vesicles/metabolism  Autism Spectrum Disorder/metabolism/physiopathology/genetics/pathology  Neurons/metabolism  Cells, Cultured  Exocytosis  Activity  Autism  Hippocampus  Presynapse  Rat  Vesicle  performed in accordance with the UK Animal (Scientific Procedures) Act 1986,  under Project and Personal Licence authority and were approved by the Animal  Welfare and Ethical Review Body at the University of Edinburgh (Home Office  project licence - 7008878). Similarly, procedures were conducted in accordance  with protocols approved by the Institutional Animal Ethics Committee of Institute  for Stem Cell Science and Regenerative Medicine, Bangalore. Consent for  publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. Index. décimale : PER Périodiques Résumé : BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment. METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1(+/-), Nlgn3(-/y), Syngap(+/-), Syngap(+/?-GAP), Pten(+/-)) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran. RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis. LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression. CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons. En ligne : https://dx.doi.org/10.1186/s13229-025-00660-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns / Shreya DAS SHARMA in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 52 p. Titre : Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns Type de document : texte imprimé Auteurs : Shreya DAS SHARMA, Auteur ; Rakhi PAL, Auteur ; Bharath Kumar REDDY, Auteur ; Bhuvaneish T. SELVARAJ, Auteur ; Nisha RAJ, Auteur ; Krishna Kumar SAMAGA, Auteur ; Durga J. SRINIVASAN, Auteur ; Loren ORNELAS, Auteur ; Dhruv SAREEN, Auteur ; Matthew R. LIVESEY, Auteur ; Gary J. BASSELL, Auteur ; Clive N. SVENDSEN, Auteur ; Peter C. KIND, Auteur ; Siddharthan CHANDRAN, Auteur ; Sumantra CHATTARJI, Auteur ; David J.A. WYLLIE, Auteur Article en page(s) : 52 p. Langues : Anglais (eng) Mots-clés : Action potential  Disease-modelling  Electrophysiology  Fragile X syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP). METHODS: Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced. RESULTS: Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca(2+)-activated K(+) currents and the persistent Na(+) current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na(+) channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines. CONCLUSIONS: Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered. En ligne : http://dx.doi.org/10.1186/s13229-020-00351-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns [texte imprimé] / Shreya DAS SHARMA, Auteur ; Rakhi PAL, Auteur ; Bharath Kumar REDDY, Auteur ; Bhuvaneish T. SELVARAJ, Auteur ; Nisha RAJ, Auteur ; Krishna Kumar SAMAGA, Auteur ; Durga J. SRINIVASAN, Auteur ; Loren ORNELAS, Auteur ; Dhruv SAREEN, Auteur ; Matthew R. LIVESEY, Auteur ; Gary J. BASSELL, Auteur ; Clive N. SVENDSEN, Auteur ; Peter C. KIND, Auteur ; Siddharthan CHANDRAN, Auteur ; Sumantra CHATTARJI, Auteur ; David J.A. WYLLIE, Auteur . - 52 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 52 p. Mots-clés : Action potential  Disease-modelling  Electrophysiology  Fragile X syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP). METHODS: Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced. RESULTS: Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca(2+)-activated K(+) currents and the persistent Na(+) current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na(+) channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines. CONCLUSIONS: Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered. En ligne : http://dx.doi.org/10.1186/s13229-020-00351-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

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

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)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 49 p. 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 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 10 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 [article] Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome [texte imprimé] / 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 10 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

FMRP and the Pathophysiology of Fragile X Syndrome / Stephanie A. BARNES  

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Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism / Natasha J. ANSTEY in Molecular Autism, 13 (2022)  

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