Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations

Autism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal and repetitive behavior patterns. Over hundreds of genes and thousands of genetic variants were reported to be highly penetrant and causative of ASD. Many of these mutations cause comorbidities such as epilep...

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Published in:Translational psychiatry 2023-07, Vol.13 (1), p.246-246, Article 246
Main Authors: Hussein, Yara, Tripathi, Utkarsh, Choudhary, Ashwani, Nayak, Ritu, Peles, David, Rosh, Idan, Rabinski, Tatiana, Djamus, Jose, Vatine, Gad David, Spiegel, Ronen, Garin-Shkolnik, Tali, Stern, Shani
Format: Article
Language:English
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Autism
Autism Spectrum Disorder - genetics
Autism Spectrum Disorder - metabolism
Behavioral Sciences
Biological Psychology
Cell Differentiation - physiology
Humans
Medicine
Medicine & Public Health
Mutation
Neurons - metabolism
Neurosciences
Pharmacotherapy
Phenotype
Psychiatry
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Summary:Autism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal and repetitive behavior patterns. Over hundreds of genes and thousands of genetic variants were reported to be highly penetrant and causative of ASD. Many of these mutations cause comorbidities such as epilepsy and intellectual disabilities (ID). In this study, we measured cortical neurons derived from induced pluripotent stem cells (iPSCs) of patients with four mutations in the genes GRIN2B , SHANK3 , UBTF , as well as chromosomal duplication in the 7q11.23 region and compared them to neurons derived from a first-degree relative without the mutation. Using a whole-cell patch-clamp, we observed that the mutant cortical neurons demonstrated hyperexcitability and early maturation compared to control lines. These changes were characterized by increased sodium currents, increased amplitude and rate of excitatory postsynaptic currents (EPSCs), and more evoked action potentials in response to current stimulation in early-stage cell development (3–5 weeks post differentiation). These changes that appeared in all the different mutant lines, together with previously reported data, indicate that an early maturation and hyperexcitability may be a convergent phenotype of ASD cortical neurons.
ISSN:2158-3188
2158-3188
DOI:10.1038/s41398-023-02535-x