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

Yara Hussein, Utkarsh Tripathi, Ashwani Choudhary, Ritu Nayak, David Peles, Idan Rosh, Tatiana Rabinski, Jose Djamus, Gad David Vatine, Ronen Spiegel, Tali Garin-Shkolnik, Shani Stern

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageAmerican English
Article number246
Pages (from-to)246
JournalTranslational Psychiatry
Volume13
Issue number1
DOIs
StatePublished - 1 Dec 2023

Keywords

  • Autism Spectrum Disorder/genetics
  • Cell Differentiation/physiology
  • Humans
  • Mutation
  • Neurons/metabolism
  • Phenotype

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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