Centre d'Information et de documentation du CRA Rhône-Alpes
CRA
Informations pratiques
-
Adresse
Centre d'information et de documentation
du CRA Rhône-Alpes
Centre Hospitalier le Vinatier
bât 211
95, Bd Pinel
69678 Bron CedexHoraires
Lundi au Vendredi
9h00-12h00 13h30-16h00Contact
Tél: +33(0)4 37 91 54 65
Mail
Fax: +33(0)4 37 91 54 37
-
Détail de l'auteur
Auteur David J. A. WYLLIE |
Documents disponibles écrits par cet auteur (2)
Faire une suggestion Affiner la recherche
Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns / Shreya DAS SHARMA in Molecular Autism, 11 (2020)
[article]
Titre : Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns Type de document : Texte imprimé et/ou numérique 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
in Molecular Autism > 11 (2020) . - 52 p.[article] Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns [Texte imprimé et/ou numérique] / 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 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)
[article]
Titre : Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism Type de document : Texte imprimé et/ou numérique 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
in Molecular Autism > 13 (2022) . - 34 p.[article] Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism [Texte imprimé et/ou numérique] / 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