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3-dimensional neural cultures (organoids) were derived from Induced Pluripotent Stem Cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. Image Credit: Yale School of Medicine

'Miniature brains' from skin cells explain autism

A larger head size — or macrocephaly — is seen in some children with severe Autism Spectrum Disorder (ASD). In a new stem cell study from the Yale School of Medicine, researchers found in ASD patients' with enlarged head size, cerebral cortex cells divided at a faster pace, and over produced the FOXG1 gene thus over producing GABAergic neurons. These observations may lead to new drug targets for autism treatment.

ASD appears during early brain development, but often lacks a clear origin or genetic basis. Recent studies of genetic mutations in rare cases of ASD, hint that development of the fetal cerebral cortex becomes abnormal with autism. A Yale research team, therefore, set out to pinpoint what goes wrong as the cerebral cortex develops.

The team simulated the early cerebral cortex using stem cells generated from ASD patient skin biopsies. They began by using standard protocols to derive pluripotent stem cells from the skin cells, in order to reset the cells to their most basic state. They then grew these stem cells into three-dimensional simulations of miniature human brains (brain organoids - the first few cell types differentiating into brain tissue). With these organoids, they could then precisely compare patient genes to other family members genes without ASD, typically fathers. All patients in the study had enlarged heads, indicating the most severe autism outcomes.

"We discovered that the patients' cells divided at a faster pace, producing more inhibitory neurons and more synapses," said Vaccarino. Her team also noted a 10-fold increase in a gene called FOXG1, important in the early growth and development of neurons in the embryonic brain.

"By regulating FOXG1 expression in patients' neural cells, we were able to reverse some of the neurobiological alterations [in the organoids].

"Correcting FOXG1 overexpression prevented overproduction of inhibitory neurons in patient's cells. We also found a link between the extent of change in gene expression [within the organoids] and the degree of a patient's macrocephaly and autism severity."

Flora Vaccarino PhD, the Harris Professor of Child Psychiatry, Professor of Neurobiology, Yale School of Medicine and lead author.

Vaccarino believes that overproduction of FOXG1 could be seen as a biomarker or molecular signature for severe ASD and become a potential drug target. The findings are published in the July 16 issue of the journal Cell.

Abstract Highlights
•iPSC-derived telencephalic organoids reflect human midfetal telencephalic development
•Inhibitory neurons are overproduced in organoids from patients with idiopathic autism
•Overproduction of inhibitory neurons is caused by increased FOXG1 gene expression

Summary
Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.

Other authors on the study included Jessica Mariani, Gianfilippo Coppola, Ping Zhang, Alexej Abyzov, Lauren Provini, Livia Tomasini, Mariangela Amenduni, Anna Szekely, Dean Palejev, Michael Wilson, Mark Gerstein, Elena Grigorenko, Katarzyna Chawarska, Kevin Pelphrey, and James Howe.

The study was funded by the National Institute of Mental Health, the State of Connecticut, and the Simons Foundation.

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