To simulate brain development in patients with autism spectrum disorder (ASD), researchers have created three-dimensional neuronal cultures using stem cells derived from patients’ skin cells. The results could help predict ASD and may even open a door to new drug targets for treatment.
According to the Yale School of Medicine researchers, this technique overcomes the challenges of understanding diseases, like autism and schizophrenia, related to the diseases’ complexity and the difficulty of studying developmental processes in human tissues.
Senior author Dr. Flora Vaccarino, the Harris professor of child psychiatry and professor of neurobiology at the Yale School of Medicine, says:
“Instead of starting from genetics, we’ve started with the biology of the disorder itself to try to get a window into the genome.”
Until now, autism researchers had to sift through patient genomes for gene mutations that could potentially explain the disorder, and then take animal or histological models to study those genes and effects on brain development. Said Dr. Flora Vaccarino:
“Brain growth abnormalities such as accelerated cell cycles, overproduction of inhibitory neurons, and synaptic overgrowth may all be precursors of a trajectory of brain development found in children with severe ASD. Our data provides a framework for studying normal human brain development and its disorders, including autism.”
The team modeled early cerebral cortex development, using stem cells generated from skin biopsies of four patients with ASD. They grew the stem cells into three-dimensional simulated miniature human brains, called brain organoids.
They then compared gene expression and developing cell types between the patients and their family members, typically fathers, without ASD. Patients in the study had enlarged heads, which indicates worse autism outcomes.
“We discovered that the patients’ cells divided at a faster pace, and that they produced more inhibitory neurons and more synapses,” Vaccarino added. She and her team also noted a 10-fold increase in a gene called FOXG1, which is important in the early growth and development of neurons in the embryonic brain.
“By regulating FOXG1 expression levels in patients’ neural cells, we were able to reverse some of the neurobiological alterations,” said Vaccarino. “Indeed, correcting the FOXG1 overexpression prevented the overproduction of inhibitory neurons in patient’s cells. Remarkably, we also found a link between the extent of change in gene expression and the degree of a patient’s macrocephaly and autism severity.”
Flora M. Vaccarino, et al
FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders
Cell Volume 162, Issue 2, p375–390, 16 July 2015
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