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 JACKSON, Auteur ; Alex CROCKER-BUQUE, Auteur ; Aoife C. MCMAHON, Auteur ; Sally M. TILL, Auteur ; Lasani S. WIJETUNGE, Auteur ; David Ja 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 JACKSON, Auteur ; Alex CROCKER-BUQUE, Auteur ; Aoife C. MCMAHON, Auteur ; Sally M. TILL, Auteur ; Lasani S. WIJETUNGE, Auteur ; David Ja 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 JACKSON, Auteur ; Alex CROCKER-BUQUE, Auteur ; Aoife C. MCMAHON, Auteur ; Sally M. TILL, Auteur ; Lasani S. WIJETUNGE, Auteur ; David Ja 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 JACKSON, Auteur ; Alex CROCKER-BUQUE, Auteur ; Aoife C. MCMAHON, Auteur ; Sally M. TILL, Auteur ; Lasani S. WIJETUNGE, Auteur ; David Ja 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

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  

Public ISBD in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA Titre : FMRP and the Pathophysiology of Fragile X Syndrome Type de document : texte imprimé Auteurs : Stephanie A. BARNES, Auteur ; Sophie R. THOMSON, Auteur ; Peter C. KIND, Auteur ; Emily K. OSTERWEIL, Auteur Année de publication : 2016 Importance : p.113-128 Langues : Anglais (eng) Mots-clés : ERK  FMR1  FMRP  Fragile X  mGluR1/5  Protein synthesis Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Fragile X syndrome (FXS) is a single-gene disorder that is the most prevalent heritable cause of intellectual disability and one of the most common single-gene causes of autism spectrum disorder (ASD). Although there is a clear genetic origin of FXS, there is still much to learn about the cellular and physiological consequences of FMR1 mutation. This knowledge is critical to the development of treatments to target the core pathophysiology of FXS. In this chapter, we summarize what is known about the function of the FMR1 gene and the encoded Fragile X mental retardation protein and describe the major cellular and neurophysiological phenotypes observed in the FXS mouse model. We then discuss evidence supporting the metabotropic glutamate receptor (mGluR) theory of Fragile X, which states that dysregulated protein synthesis downstream of mGluR1/5 is a core contributor to the pathogenesis of FXS. The remainder of the chapter will be devoted to discussing the clinical implications of this research and its relevance to the wider ASD population. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00008-X Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA FMRP and the Pathophysiology of Fragile X Syndrome [texte imprimé] / Stephanie A. BARNES, Auteur ; Sophie R. THOMSON, Auteur ; Peter C. KIND, Auteur ; Emily K. OSTERWEIL, Auteur . - 2016 . - p.113-128. Langues : Anglais (eng) Mots-clés : ERK  FMR1  FMRP  Fragile X  mGluR1/5  Protein synthesis Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Fragile X syndrome (FXS) is a single-gene disorder that is the most prevalent heritable cause of intellectual disability and one of the most common single-gene causes of autism spectrum disorder (ASD). Although there is a clear genetic origin of FXS, there is still much to learn about the cellular and physiological consequences of FMR1 mutation. This knowledge is critical to the development of treatments to target the core pathophysiology of FXS. In this chapter, we summarize what is known about the function of the FMR1 gene and the encoded Fragile X mental retardation protein and describe the major cellular and neurophysiological phenotypes observed in the FXS mouse model. We then discuss evidence supporting the metabotropic glutamate receptor (mGluR) theory of Fragile X, which states that dysregulated protein synthesis downstream of mGluR1/5 is a core contributor to the pathogenesis of FXS. The remainder of the chapter will be devoted to discussing the clinical implications of this research and its relevance to the wider ASD population. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00008-X Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301

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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)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 34 p. Titre : Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism Type de document : texte imprimé Auteurs : Natasha J. ANSTEY, Auteur ; Vijayakumar KAPGAL, Auteur ; Shashank TIWARI, Auteur ; Thomas C. WATSON, Auteur ; Anna K. H. TOFT, Auteur ; Owen R. DANDO, Auteur ; Felicity H. INKPEN, Auteur ; Paul S. BAXTER, Auteur ; Zrinko KOZIĆ, Auteur ; Adam D. JACKSON, Auteur ; Xin HE, Auteur ; Mohammad SARFARAZ NAWAZ, Auteur ; Aiman KAYENAAT, Auteur ; Aditi BHATTACHARYA, Auteur ; David J. A. WYLLIE, Auteur ; Sumantra CHATTARJI, Auteur ; Emma R. WOOD, Auteur ; Oliver HARDT, Auteur ; Peter C. KIND, Auteur Article en page(s) : 34 p. Langues : Anglais (eng) Mots-clés : Animals  Autistic Disorder/metabolism  Fear/physiology  Freezing  Humans  Neurons/physiology  Periaqueductal Gray/metabolism  Rats  Autism  Fear  Flight  Intellectual disability  Neuroligin-3  Periaqueductal grey Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. METHODS: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3(-/y) rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3(-/y) rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). RESULTS: We observed that, unlike the wildtype, Nlgn3(-/y) rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3(-/y) rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3(-/y) than wildtype rats, indicating the functional impact of the increased cellular excitability. LIMITATIONS: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. CONCLUSIONS: We describe altered fear responses in Nlgn3(-/y) rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00511-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 [article] Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism [texte imprimé] / Natasha J. ANSTEY, Auteur ; Vijayakumar KAPGAL, Auteur ; Shashank TIWARI, Auteur ; Thomas C. WATSON, Auteur ; Anna K. H. TOFT, Auteur ; Owen R. DANDO, Auteur ; Felicity H. INKPEN, Auteur ; Paul S. BAXTER, Auteur ; Zrinko KOZIĆ, Auteur ; Adam D. JACKSON, Auteur ; Xin HE, Auteur ; Mohammad SARFARAZ NAWAZ, Auteur ; Aiman KAYENAAT, Auteur ; Aditi BHATTACHARYA, Auteur ; David J. A. WYLLIE, Auteur ; Sumantra CHATTARJI, Auteur ; Emma R. WOOD, Auteur ; Oliver HARDT, Auteur ; Peter C. KIND, Auteur . - 34 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 34 p. Mots-clés : Animals  Autistic Disorder/metabolism  Fear/physiology  Freezing  Humans  Neurons/physiology  Periaqueductal Gray/metabolism  Rats  Autism  Fear  Flight  Intellectual disability  Neuroligin-3  Periaqueductal grey Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. METHODS: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3(-/y) rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3(-/y) rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). RESULTS: We observed that, unlike the wildtype, Nlgn3(-/y) rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3(-/y) rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3(-/y) than wildtype rats, indicating the functional impact of the increased cellular excitability. LIMITATIONS: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. CONCLUSIONS: We describe altered fear responses in Nlgn3(-/y) rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00511-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491

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