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Using induced pluripotent stem cells (iPSCs) from patients with autism spectrum disorder (ASD) and unaffected family members to grow 3-dimensional neural cultures (organoids) that recapitulate first trimester brain development, investigators at Yale University in New Haven have gained insights into early development of the autistic brain (Mariani J et al. Cell. 2015;162:375-390).
Compared with brain organoids derived from unaffected family members, those from 4 patients with idiopathic ASD displayed a variety of neurodevelopmental differences, including altered expression of genes controlling neuronal development, up-regulated cell proliferation, overproduction of inhibitory neurons, and altered synaptic development. Autism spectrum disorder–derived organoids also appeared to overproduce inhibitory GABAergic neurons. By attenuating the expression of a single gene encoding the transcription factor FOXG1, the researchers were able to restore differentiation of the inhibitory neurons to normal levels.
The findings suggest unbalanced inhibitory neural differentiation caused by overexpression of FOXG1 may be a shared pathophysiological marker of idiopathic ASD.