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Increased Ca2+ signaling in NRXN1α +/- neurons derived from ASD induced pluripotent stem cells.

ABSTRACT: 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 NRXN1α +/- deletions. Seven control and six NRXN1α +/- iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca2+) imaging was performed using Fluo4-AM, and the properties of Ca2+ transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with NRXN1α +/- neurons. Results:NRXN1α +/- neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca2+ 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 NRXN1α +/- neurons identified by STRING and GSEA analyses. Conclusions:This is the first report to show that human NRXN1α +/- neurons derived from ASD patients' iPSCs present novel phenotypes of upregulated VGCCs and increased Ca2+ transients, which may facilitate the development of drug screening assays for the treatment of ASD.

SUBMITTER: Avazzadeh S

PROVIDER: S-EPMC6937972 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Increased Ca2+ signaling in NRXN1α+/- neurons derived from ASD induced pluripotent stem cells.

Avazzadeh Sahar S McDonagh Katya K Reilly Jamie J Wang Yanqin Y Boomkamp Stephanie D SD McInerney Veronica V Krawczyk Janusz J Fitzgerald Jacqueline J Feerick Niamh N O'Sullivan Matthew M Jalali Amirhossein A Forman Eva B EB Lynch Sally A SA Ennis Sean S Cosemans Nele N Peeters Hilde H Dockery Peter P O'Brien Timothy T Quinlan Leo R LR Gallagher Louise L Shen Sanbing S

Molecular autism 20191230

<h4>Background</h4>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 NRXN ...[more]

PMID: 31893021

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Project description:BackgroundNRXN1 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.MethodsIn 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.ResultsNRXN1α+/- 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.ConclusionsTogether 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.

Dataset Information

Increased Ca2+ signaling in NRXN1α +/- neurons derived from ASD induced pluripotent stem cells.

Publications

Increased Ca<sup>2+</sup> signaling in <i>NRXN1α</i><sup><i>+/-</i></sup> neurons derived from ASD induced pluripotent stem cells.

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