Journal
BIOLOGICAL PSYCHIATRY
Volume 89, Issue 5, Pages 486-496Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2020.06.014
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Funding
- European Autism Interventions (EU-AIMS)
- AIMS-2-TRIALS: the Innovative Medicines Initiative Joint Undertaking [115300]
- European Union's Seventh Framework Programme (FP7/2007-2013)
- Innovative Medicines Initiative joint undertaking [115439-2]
- European Union's Seventh Framework Programme (FP7-HEALTH) [603016]
- Wellcome Trust Institutional Strategic Support Fund Grant [097819]
- King's Health Partners Research and Development Challenge Fund
- Guy's and St. Thomas' Charity [R130587]
- Independent Investigator's Award from the Brain and Behavior Foundation [25957]
- Medical Research Council, United Kingdom [MR/N026063/1]
- Mortimer D. Sackler Foundation
- Autism Research Trust
- Chinese University of Hong Kong
- Templeton World Charitable Foundation
- Wellcome Trust
- Jawaharlal Nehru Memorial Trust
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The study suggests that autism-iPSCs diverge from control-iPSCs at a cellular level during early neurodevelopment, indicating unique developmental differences associated with autism may be established at early prenatal stages.
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 controland 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.
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