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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 (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  NRXN1α   +/−   neurons.    Results   NRXN1α   +/−   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  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 Ca 2+  transients, which may facilitate the development of drug screening assays for the treatment of ASD.

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