Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals

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.