Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals

Dwaipayan Adhya, Vivek Swarup, Roland Nagy, Lucia Dutan, Carole Shum, Eva P. Valencia-Alarcón, Kamila Maria Jozwik, Maria Andreina Mendez, Jamie Horder, Eva Loth, Paulina Nowosiad, Irene Lee, David Skuse, Frances A. Flinter, Declan Murphy, Grainne McAlonan, Daniel H. Geschwind, Jack Price, Jason Carroll, Deepak P. Srivastava*Simon Baron-Cohen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Background: Autism is a heterogeneous collection of disorders with a complex molecular underpinning. Evidence from postmortem brain studies have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from individuals with autism with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism. Methods: iPSCs were generated from 9 unrelated individuals with autism without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing control individuals. iPSCs were differentiated toward either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterize iPSCs at different stages of differentiation. Results: A subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to postmortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated toward a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs. Conclusions: Taken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.

Original languageEnglish
JournalBiological psychiatry
DOIs
Publication statusAccepted/In press - 1 Jan 2020

Keywords

  • Autism
  • Cortical differentiation
  • Functional genomics
  • Midbrain differentiation
  • Neural precursors
  • Neural progenitor cells
  • Neurodevelopment

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