NRXN1α +/- is associated with increased excitability in ASD iPSC-derived neurons.

Autor: Avazzadeh S; School of Medicine, Regenerative Medicine Institute, Biomedical Science Building BMS-1021, National University of Ireland Galway, Dangan, Ireland., Quinlan LR; Physiology and Cellular Physiology Research Laboratory, School of Medicine, CÚRAM SFI Centre for Research in Medical Devices, National University of Ireland (NUI), Galway, Ireland., Reilly J; School of Medicine, Regenerative Medicine Institute, Biomedical Science Building BMS-1021, National University of Ireland Galway, Dangan, Ireland., McDonagh K; School of Medicine, Regenerative Medicine Institute, Biomedical Science Building BMS-1021, National University of Ireland Galway, Dangan, Ireland., Jalali A; School of Mathematical Sciences, University College Cork, Cork, Ireland., Wang Y; School of Medicine, Regenerative Medicine Institute, Biomedical Science Building BMS-1021, National University of Ireland Galway, Dangan, Ireland.; Department of Physiology, College of Life Science, Hebei Normal University, Shijiazhuang, China., McInerney V; HRB Clinical Research Facility, National University of Ireland (NUI), Galway, Ireland., Krawczyk J; Department of Haematology, Galway University Hospital, Galway, Ireland., Ding Y; School of Medicine, Regenerative Medicine Institute, Biomedical Science Building BMS-1021, National University of Ireland Galway, Dangan, Ireland., Fitzgerald J; Trinity Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland., O'Sullivan M; Trinity Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland., Forman EB; Children's University Hospital, Temple Street, Dublin, Ireland., Lynch SA; Children's University Hospital, Temple Street, Dublin, Ireland.; Department of Clinical Genetics, OLCHC, Dublin 12, Ireland., Ennis S; School of Medicine and Medical Science, UCD Academic Centre On Rare Diseases, University College Dublin, Dublin, Ireland., Feerick N; Centre for Bioengineering, Trinity College Institute of Neuroscience, School of Medicine, School of Engineering, Trinity College Dublin, Dublin, Ireland., Reilly R; Centre for Bioengineering, Trinity College Institute of Neuroscience, School of Medicine, School of Engineering, Trinity College Dublin, Dublin, Ireland., Li W; Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China., Shen X; School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China., Yang G; College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China., Lu Y; College of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China., Peeters H; Centre for Human Genetics, University Hospital Leuven, KU Leuven, 3000, Leuven, Belgium., Dockery P; Centre for Microscopy and Imaging, Anatomy, School of Medicine, National University of Ireland (NUI), Galway, Ireland., O'Brien T; School of Medicine, Regenerative Medicine Institute, Biomedical Science Building BMS-1021, National University of Ireland Galway, Dangan, Ireland., Shen S; School of Medicine, Regenerative Medicine Institute, Biomedical Science Building BMS-1021, National University of Ireland Galway, Dangan, Ireland. sanbing.shen@nuigalway.ie.; FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, D02, Ireland. sanbing.shen@nuigalway.ie., Gallagher L; Trinity Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
Jazyk: angličtina
Zdroj: BMC neuroscience [BMC Neurosci] 2021 Sep 15; Vol. 22 (1), pp. 56. Date of Electronic Publication: 2021 Sep 15.
DOI: 10.1186/s12868-021-00661-0
Abstrakt: Background: NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α +/- and showed increased calcium transients in patient neurons.
Methods: In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α +/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism.
Results: NRXN1α +/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α +/- cortical neurons.
Conclusions: Together with recent evidence of increased calcium transients, our results showed that human NRXN1α +/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α +/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.
(© 2021. The Author(s).)
Databáze: MEDLINE
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