Increased Ca(2+) signaling in NRXN1alpha (+/-) neurons derived from ASD induced pluripotent stem cells / S. AVAZZADEH in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 52 p. Titre : Increased Ca(2+) signaling in NRXN1alpha (+/-) neurons derived from ASD induced pluripotent stem cells Type de document : Texte imprimé et/ou numérique Auteurs : S. AVAZZADEH, Auteur ; K. MCDONAGH, Auteur ; J. REILLY, Auteur ; Y. WANG, Auteur ; S. D. BOOMKAMP, Auteur ; V. MCINERNEY, Auteur ; J. KRAWCZYK, Auteur ; J. FITZGERALD, Auteur ; N. FEERICK, Auteur ; M. O'SULLIVAN, Auteur ; A. JALALI, Auteur ; E. B. FORMAN, Auteur ; S. A. LYNCH, Auteur ; S. ENNIS, Auteur ; N. COSEMANS, Auteur ; H. PEETERS, Auteur ; P. DOCKERY, Auteur ; T. O'BRIEN, Auteur ; L. R. QUINLAN, Auteur ; L. GALLAGHER, Auteur ; S. SHEN, Auteur Article en page(s) : 52 p. Langues : Anglais (eng) Mots-clés : Autism  Calcium signaling  Induced pluripotent stem cells  NRXN1alpha  Neurons  Transcriptome Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high co-morbidity of epilepsy and associated with hundreds of rare risk factors. NRXN1 deletion is among the commonest rare genetic factors shared by ASD, schizophrenia, intellectual disability, epilepsy, and developmental delay. However, how NRXN1 deletions lead to different clinical symptoms is unknown. Patient-derived cells are essential to investigate the functional consequences of NRXN1 lesions to human neurons in different diseases. Methods: Skin biopsies were donated by five healthy donors and three ASD patients carrying NRXN1alpha (+/-) deletions. Seven control and six NRXN1alpha (+/-) iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca(2+)) imaging was performed using Fluo4-AM, and the properties of Ca(2+) transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with NRXN1alpha (+/-) neurons. Results: NRXN1alpha (+/-) neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca(2+) transients. Whole genome RNA sequencing also revealed altered ion transport and transporter activity, with upregulated voltage-gated calcium channels as one of the most significant pathways in NRXN1alpha (+/-) neurons identified by STRING and GSEA analyses. Conclusions: This is the first report to show that human NRXN1alpha (+/-) neurons derived from ASD patients' iPSCs present novel phenotypes of upregulated VGCCs and increased Ca(2+) transients, which may facilitate the development of drug screening assays for the treatment of ASD. En ligne : http://dx.doi.org/10.1186/s13229-019-0303-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 [article] Increased Ca(2+) signaling in NRXN1alpha (+/-) neurons derived from ASD induced pluripotent stem cells [Texte imprimé et/ou numérique] / S. AVAZZADEH, Auteur ; K. MCDONAGH, Auteur ; J. REILLY, Auteur ; Y. WANG, Auteur ; S. D. BOOMKAMP, Auteur ; V. MCINERNEY, Auteur ; J. KRAWCZYK, Auteur ; J. FITZGERALD, Auteur ; N. FEERICK, Auteur ; M. O'SULLIVAN, Auteur ; A. JALALI, Auteur ; E. B. FORMAN, Auteur ; S. A. LYNCH, Auteur ; S. ENNIS, Auteur ; N. COSEMANS, Auteur ; H. PEETERS, Auteur ; P. DOCKERY, Auteur ; T. O'BRIEN, Auteur ; L. R. QUINLAN, Auteur ; L. GALLAGHER, Auteur ; S. SHEN, Auteur . - 52 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 52 p. Mots-clés : Autism  Calcium signaling  Induced pluripotent stem cells  NRXN1alpha  Neurons  Transcriptome Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high co-morbidity of epilepsy and associated with hundreds of rare risk factors. NRXN1 deletion is among the commonest rare genetic factors shared by ASD, schizophrenia, intellectual disability, epilepsy, and developmental delay. However, how NRXN1 deletions lead to different clinical symptoms is unknown. Patient-derived cells are essential to investigate the functional consequences of NRXN1 lesions to human neurons in different diseases. Methods: Skin biopsies were donated by five healthy donors and three ASD patients carrying NRXN1alpha (+/-) deletions. Seven control and six NRXN1alpha (+/-) iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca(2+)) imaging was performed using Fluo4-AM, and the properties of Ca(2+) transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with NRXN1alpha (+/-) neurons. Results: NRXN1alpha (+/-) neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca(2+) transients. Whole genome RNA sequencing also revealed altered ion transport and transporter activity, with upregulated voltage-gated calcium channels as one of the most significant pathways in NRXN1alpha (+/-) neurons identified by STRING and GSEA analyses. Conclusions: This is the first report to show that human NRXN1alpha (+/-) neurons derived from ASD patients' iPSCs present novel phenotypes of upregulated VGCCs and increased Ca(2+) transients, which may facilitate the development of drug screening assays for the treatment of ASD. En ligne : http://dx.doi.org/10.1186/s13229-019-0303-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414

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