Sunday, July 19, 2015

Autism and brain organoids

Using stem cells derived from patients' skin cells, researchers have created three-dimensional neuronal cultures to mimic brain development in patients with Autism Spectrum Disorder (ASD). These so-called "brain organoids" revealed an excess of inhibitory cells and increased neuronal connections, which the scientists were then able to correct by suppressing the expression of one gene, FOXG1.

Although genetic variations and environmental factors are known to contribute to risk for ASD, about 80% of cases still lack clear etiologies or pathogenic models. By studying the growth of 3D brain cell cultures made from human stem cells, the researchers got an unprecedented look at how this disorder might arise during early fetal brain development (up to 16 weeks post conception). They studied four families that had at least one member who had ASD with an enlarged brain -- a feature associated with severe autism that occurs in about 20% of people with the disorder...

Not knowing the genetics behind ASD, the researchers decided to look at how cells from different patients develop. They figured that even if the genes are not the same, there may be something in common with cell development. "Indeed, we found that there are abnormalities that are shared in neurodevelopment," Vaccarino said. The study also found that the biological measures were correlated with later developmental symptoms.

But most importantly, the scientists were able to fix the observed neuronal imbalance in their brain organoids by suppressing a single gene. This suggests that it may be possible to restore neuronal balance in living human brains via clinical intervention.

"This study provides valuable insights into autism by suggesting a bias in favor of the production of inhibitory neurons caused by a particular gene," Manuel Casanova, MD, told MedPage Today in an email. "The implications of this study and the doors it opens for future studies are incredibly large and significant."...

The researchers also hope to figure out exactly what caused the gene expression alterations and neuronal imbalances found in their study. It could be a genetic mutation or some other epigenetic change.

Once scientists have a better understanding of the neurobiological abnormalities in ASD and other developmental disorders, "then we can try ways to correct this with medicine," she added.

Though Casanova felt the study was incredibly important and well-done, he mentioned that it did have some limitations. Other than the small sample size, he expressed concern over the validity of using such a 3D cell culture to model an entire human brain. "The way neurons aggregate in these cultures ... may bear little resemblance to the circuitry observed in the human brain."

"Still, the idea of simplifying research in autism by studying a reductionist model of the brain is commendable."

http://www.medpagetoday.com/Neurology/Autism/52635?xid=nl_mpt_DHE_2015-07-18&eun=g906366d0r

Jessica Mariani, Gianfilippo Coppola, Ping Zhang, Alexej Abyzov, Lauren Provini, Livia Tomasini, Mariangela Amenduni, Anna Szekely, Dean Palejev, Michael Wilson, Mark Gerstein, Elena L. Grigorenko, Katarzyna Chawarska, Kevin A. Pelphrey, James R. Howe, Flora M. Vaccarino.  Cell Volume 162, Issue 2, p375–390, 16 July 2015
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.

 
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Jessica Mariani


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Gianfilippo Coppola


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Ping Zhang


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Lauren Provini


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Mariangela Amenduni


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Dean Palejev


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Mark Gerstein


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Katarzyna Chawarska


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