Brain cells, interrupted: How some genes may cause autism, epilepsy and schizophrenia
A team of researchers has developed a new way to study how genes may cause autism and other neurodevelopmental disorders: by growing tiny brain-like structures in the lab and tweaking their DNA.
These "assembloids," described in the journal Nature, could one day help researchers develop targeted treatments for autism spectrum disorder, intellectual disability, schizophrenia, and epilepsy.
"This really accelerates our effort to try to understand the biology of psychiatric disorders," says Dr. Sergiu Pașca, a professor of psychiatry and behavioral sciences at Stanford University and an author of the study.
The research suggests that someday "we'll be able to predict which pathways we can target to intervene" and prevent these disorders, adds Kristen Brennand, a professor of psychiatry at Yale who was not involved in the work.
The study comes after decades of work identifying hundreds of genes that are associated with autism and other neurodevelopmental disorders. But scientists still don't know how problems with these genes alter the brain.
"The challenge now is to figure out what they're actually doing, how disruptions in these genes are actually causing disease," Pașca says. "And that has been really difficult."
For ethical reasons, scientists can't just edit a person's genes to see what happens. They can experiment on animal brains, but lab animals like rodents don't really develop anything that looks like autism or schizophrenia.
So Pașca and a team of scientists tried a different approach, which they detailed in their new paper.
The team did a series of experiments using tiny clumps of human brain cells calledbrain organoids. These clumps will grow for a year or more in the lab, gradually organizing their cells much the way a developing brain would. And by exposing an organoid to certain growth factors, scientists can coax it into resembling tissue found in brain areas including the cortex and hippocampus.
"We can actually make different parts of the nervous system in a dish fromstem cells," Pașca says. When these parts are placed in the same dish, they will even form connections, much like an actual brain. The resulting structure is called anassembloid.
Pașca's team thought they could use assembloids to study how developmental disorder genes affect special brain cells called interneurons, which are thought to play a role in several psychiatric disorders.
During pregnancy and the first two years of life, these special cells must complete a remarkable journey.
"Interneurons are born in deep regions of the brain, and then they have to migrate all the way to the cortex," Pașca says. "So you can imagine that during that migration a lot of things could go awry."
Pașca's team simulated the migration of interneurons by creating assembloids containing two types of organoids. One resembled an area deep in the brain called the subpallium, where most interneurons are generated. The other organoid resembled the cerebral cortex, where interneurons are supposed to end up.
"And then we've put them together, allowing these interneurons to move towards the cerebral cortex," he says.
The process worked just the way it's supposed to in assembloids containing typical organoids. So next, the team used a gene-editing technique called CRISPR to alter the organoids.
This approach allowed the team to study the effect of more than 400 genes associated with neurodevelopmental disorders. And they found that 46 of those genes were involved in either the generation of interneurons, or with their migration. Knock out a part of those genes and interneurons no longer arrived where they were supposed to.
In the cerebral cortex, interneurons serve as inhibitory neurons, which means they act a bit like the brake in a car. The interneurons can release a neurotransmitter that tells other neurons to reduce their activity.
Meanwhile, excitatory neurons act as the accelerator, telling other cells to become more active.
Brain networks rely on a delicate balance between excitatory and inhibitory neurons. Too much acceleration and the result can be an epileptic seizure. Too much brake and vital information may get lost or delayed.
The study is important because it offers a way for scientists to study the effect of many genes at the same time, and identify the ones that affect a particular type of cell or cell function during brain development, says Dr. Guo-li Ming, a professor of neuroscience at the University of Pennsylvania's Perelman School of Medicine.
The research also shows clearly how gene variants could lead to autism or some other neurodevelopmental disorder by disturbing interneurons.
"That would be a disaster" in a developing brain, Ming says. "The circuitry would be wrong and the signaling would be wrong, and ultimately the brain functioning would be wrong."
Ming, who was not connected with study, says her lab would like to use the combination of assembloids and CRISPR in their own research on schizophrenia, another psychiatric disorder with a neurodevelopmental origin.
Pașca's study could help brain scientists make the sort of advances that cancer researchers have in the past few decades, says Brennand.
"Thirty years ago, we might have thought all intestinal cancers should be treated the same way and all lung cancers should be treated the same way," she says. "Now we know a lot better."
Instead of choosing treatments according to the location of a cancer, doctors study a tumor's genes to determine which therapy is most likely to work. A similar approach could eventually help people with autism spectrum disorder, epilepsy, and schizophrenia, Brennand says.
"This improved genetic understanding will let us do better," she says, "because we'll know which pathways we can target to intervene."
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