A research team is studying the influence of genes on autism and have found that the absence of certain genes leads to an imbalance.
Stanford – Researchers at Stanford University used a variety of high-tech instruments to simulate brain development in a laboratory dish and discovered several dozen genes that disrupt crucial steps in the process, potentially leading to autism, a spectrum of disorders that is about one of It affects 36 Americans and affects the ability to communicate and interact with others.
The in the specialist journal Nature published results are the result of ten years of work and could one day pave the way for scientists to develop treatments that allow these phases of brain development to go through undisturbed.
The study addresses a 20-year-old theory that a cause of autism may be a disruption in the delicate balance between two types of nerve cells in the brain’s cerebral cortex, the area responsible for higher-level processes such as thinking, emotions, decision-making and language is responsible.
Excessive excitation of cells can impair concentration
Some nerve cells in this region of the brain excite other nerve cells and cause them to fire; other cells, called interneurons, do the opposite. Too much arousal can affect concentration in the brain and cause epilepsy, a seizure disorder that is more common in people with autism than in the general population. Scientists therefore believe that more inhibitory interneurons are required for proper balance.
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In the developing fetus, these nerve cells begin deep in the brain in a region called the subpallium and then slowly migrate to the cerebral cortex. The process begins in mid-pregnancy and ends in the child’s second year of life, according to Sergiu Pasca, a professor of psychiatry and behavioral sciences at Stanford University and leader of the study.
Pasca’s team, which included researchers from the University of California at San Francisco and the Icahn School of Medicine at Mount Sinai, examined 425 genes associated with neurodevelopmental disorders to determine which genes affect the formation and migration of interneurons . Among the genes identified in the study were those associated with autism.
“The great thing about this work is that autism is a collection of different behaviors, but we don’t know how these behaviors are related to differences in the brain,” said James McPartland, a professor of child psychiatry and psychology at Yale School of Medicine, who did not attend was involved in the study.
The new work advances autism research by “beginning to provide a fundamental understanding of the building blocks of brain development,” he said.
Autism research: Scientists test 425 genes at once
For ethical reasons, it is not possible to observe the developmental processes in a fetal brain. Instead, scientists can often learn the role of a single gene by observing what happens when that gene is turned off in a laboratory dish of cells. However, knocking out 425 genes one at a time is time-consuming.
For their study, Pasca and his colleagues used a technique they developed six years ago that allowed them to test all 425 genes at once. They changed the cells so that only the nerve cells that prevent others from firing glow green. They also used the gene editing system CRISPR to create different cells, each missing one of the 425 genes.
The scientists created clumps of cells that mimic the structures and functions of the brain’s subpallium and cerebral cortex. They then placed the two different clumps next to each other in a laboratory dish.
“We discovered that if you place them in close proximity to each other, they immediately fuse together,” says Pasca. “And the cells know exactly what to do… and they invade the cortex just like they would in humans.”
This is all the more remarkable because in living brains the region of the subpallium, in which interneurons are formed, is not directly next to the cerebral cortex, but is only a few centimeters away from it, says Pasca.
13 missing genes prevent the formation of interneurons
Pasca and his colleagues gave the interneurons time to form and migrate to the cerebral cortex. They then examined the genetic profiles of the different cells. This enabled them to identify the genes that caused two defects: the lack of formation of interneurons and the failure of interneurons to migrate to the cerebral cortex.
They found 13 genes whose absence prevents the formation of interneurons. They identified an additional 33 genes whose absence prevented interneurons from migrating to the cerebral cortex. In total, 46 genes – 11 percent of the 425 genes associated with neurodevelopmental disorders – appeared to affect nerve cells inhibiting their neighbors, causing an imbalance.
The scientists found that one of the genes crucial for interneuron migration, LNPK, was linked to seizure disorders. This would support the idea that seizures are caused by too much excitation of neurons and too little inhibition.
Using the fused clumps of cells, the researchers conducted “by far the largest screening for autism and [Neuroentwicklungsstörungs-]genes,” Guo-li Ming, a professor in the departments of neuroscience and psychiatry at the University of Pennsylvania, wrote in an email commenting on the study.
Ming, who was not involved in the project, called it a “tour de force” that could one day lead to researchers developing treatments for autism and other disorders – therapies based on an individual patient’s genetic profile .
Experts emphasized that autism is not a single disease, but a group of disorders. Neuron imbalance is just one of several possible causes.
For example, many people with autism have defects in microglia, cells that regulate brain development, repair of injuries and maintenance of the networks that process information.
Genes alone cannot explain autism
And genes alone can’t explain autism, says Yale’s McPartland. “It’s complicated and it’s fascinating. One can [Autismus bei] have identical twins, and they will almost always both have autism. But not always.”
Jennifer Singh, an autism expert and associate professor in the school of history and sociology at the Georgia Institute of Technology, said too much money has been spent searching for the genetic basis of autism spectrum disorder. Singh pointed to a 2018 report from a federal advisory committee that found that 60 percent of funding for autism research is focused on biology and risk factors, but only 2 percent is focused on “lifespan issues” for people living with the disorder spectrum.
“This excessive focus and massive investment obscures the true issues facing people with autism and their families,” Singh wrote in an email. She referred to the “autism cliff” that occurs when people with autism can no longer attend public school. “Services that would be useful for autistic adults do not exist or are no longer available,” she said.
Pasca said it was important to “examine the natural history of the disease. But we also need to understand the biological basis if we are to be effective [Behandlungen] want to develop”.
To the author
Mark Johnson joined The Washington Post in July 2022 after 22 years at the Milwaukee Journal Sentinel, where he covered health and science. He wrote about the first person to survive rabies without vaccination and reported the first use of whole gene sequencing to diagnose and treat a new disease.
We are currently testing machine translations. This article was automatically translated from English into German.
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