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Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals

Dwaipayan Adhya1, Vivek Swarup2, Roland Nagy3

  • 1Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Biological Psychiatry
|August 23, 2020
PubMed

Insights

Autism-derived stem cells show early prenatal cellular differences in brain development, suggesting these alterations occur before birth. This research sheds light on the origins of autism spectrum disorder at a cellular level.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a poorly understood molecular basis.
  • Evidence suggests prenatal developmental alterations contribute to autism, but early cellular events remain largely unknown.
  • Previous studies using induced pluripotent stem cells (iPSCs) from individuals with autism and macrocephaly pointed to prenatal development as a critical period.

Purpose of the Study:

  • To investigate early cellular events during prenatal neurodevelopment in autism using iPSCs.
  • To identify autism-specific cellular phenotypes and gene expression signatures in differentiating neurons.
  • To compare cellular differentiation trajectories between iPSCs from individuals with autism and typically developing controls.

Main Methods:

  • Generated iPSCs from 9 individuals with autism (without macrocephaly) and 6 typically developing controls.
  • Differentiated iPSCs into cortical and midbrain neuronal fates.
  • Utilized RNA sequencing and high-throughput cellular phenotyping to analyze iPSCs at various differentiation stages.

Main Results:

  • Autism-iPSC-derived cortical neurons exhibited gene expression patterns similar to postmortem brain studies, suggesting a common biological mechanism.
  • Autism-iPSCs showed impaired neural rosette formation and altered cell type assignment during cortical differentiation.
  • These cellular differences occurred independently of changes in cell proliferation, distinguishing them from prior findings.

Conclusions:

  • Autism-iPSCs exhibit distinct cellular behaviors compared to control-iPSCs early in neurodevelopment.
  • These findings support the hypothesis that autism-associated developmental differences are established during early prenatal stages.
  • The study highlights the utility of iPSCs in modeling early prenatal cellular pathology in autism.
Abstract

Keywords:
AutismCortical differentiationFunctional genomicsMidbrain differentiationNeural precursorsNeural progenitor cellsNeurodevelopment

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