Using Skin-Cell Research to Probe Cellular Basis of Autism
Emerging research has advanced knowledge of autism by studying brainlike spheres grown in an elaborate process from skin cells.
Neuroscientists at Stanford University School of Medicine studied cells from patients with Timothy syndrome, a rare genetic condition that is associated with one of the most penetrant forms of autism: In other words, most people with the Timothy syndrome mutation have autism as a symptom, among other problems.
Autism is a spectrum of developmental disorders of impaired social and verbal interaction. Unfortunately, medical science has not developed a method to treat the underlying causes of autism. Consequently, understanding what goes awry in autistic brain development is an area of considerable investigation.
In the current study, scientists hypothesize that the autism in Timothy syndrome patients is caused by a gene mutation that interferes with the communication of nerve cells.
Specifically, scientists believe the gene mutation makes calcium channels in neuron membranes defective, interfering with how those neurons communicate and develop.
The flow of calcium into neurons enables them to fire, and the way that the calcium flow is regulated is a pivotal factor in how our brains function.
Researchers also found brain cells grown from individuals with Timothy syndrome resulted in fewer of the kind of cells that connect both halves of the brain, as well as an overproduction of two of the brain’s chemical messengers, dopamine and norepinephrine. Furthermore, they found they could reverse these effects by chemically blocking the faulty channels.
Sergiu Pasca, M.D., and Ricardo Dolmetsch, Ph.D., led the study, which is published online in Nature Medicine.
According to researchers, the gaps in our understanding of the causes of psychiatric disorders such as autism have made them difficult to treat. Naturally, research on autism and other psychiatric and neurological diseases is limited by the inability to sample and experiment on living brain tissues.
To address this, Dolmetsch and his colleagues used a novel approach involving what are known as induced pluripotent stem cells, or iPS cells.
“We developed a way of taking skin cells from humans with Timothy syndrome and converting them into stem cells, then converting those stem cells into neurons,” said Dolmetsch. The scientists grew these iPS cells as free-floating clumps in a nutrient-rich solution, later transferring the clumps to tissue culture plates.
In the medium, some of the plates developed three-dimensional, brainlike spheres whose cells later migrated outward and matured into neurons.
These neurons formed three distinct layers, a good first approximation of living tissue in the brain. By visualizing these neurons under a microscope and quantifying their gene expression, the scientists were able to characterize at the cellular level abnormalities that may be associated with autism.
The neurons grown from Timothy-syndrome iPS cells showed larger-than-normal spikes in calcium levels, suggesting the calcium channels lost their ability to shut off. This set off dramatic changes in neuronal signaling, reconfiguring how genes were expressed.
The finding reinforces the view that autism results from defects in brain connectivity.
Pasca and Dolmetsch had an “aha” moment when they realized the neurons grown from Timothy syndrome cells were making too much of the enzyme most critical for producing dopamine and norepinephrine, which play an important role in sensory processing and social behavior. The realization may offer important clues about what causes the problems seen in autism.
To determine whether the enzyme upsurge was reversible, the scientists treated the neurons with a chemical that blocks the defective calcium channels, called roscovitine.
They saw a nearly 70 percent reduction in the proportion of cells producing the enzyme, confirming the defective calcium channel was the culprit in producing too much dopamine and norepinephrine. Such reversibility suggests that certain cellular abnormalities in autism may be treatable.
Dolmetsch warned, however, that roscovitine is not currently approved for use in humans and has never been tested in children. While it is currently in clinical trials for lung cancer, it reportedly causes nausea and other side effects.
“The reported side effects are probably due to the fact that, in addition to targeting the channel that is mutated in autism, roscovitine also inhibits kinases that are required for cell proliferation,” he said. “We think that roscovitine is a good starting point, but probably has to be optimized before it would be useful for autism.”
In the meantime, the study represents a major achievement with its success in developing a technique to recreate how the neurons of individuals with Timothy syndrome develop in a lab setting. It’s the first time it’s been possible to study the disorder in human cells rather than mouse cells, so it represents a better clinical model, Dolmetsch said.
“These results could lead to a very powerful research tool,” he said. “It’s human psychiatric disease in a petri dish.”
Nauert PhD, R. (2015). Using Skin-Cell Research to Probe Cellular Basis of Autism. Psych Central. Retrieved on April 27, 2017, from https://psychcentral.com/news/2011/11/28/using-skin-cell-research-to-probe-cellular-basis-of-autism/31942.html