That’s one theory for cognitive differences in people with autism. “There are indications that there is a balance between bottom-up sensation and modulation,” said Matthew Belmonte, who studies neurophysiology and behavior in autism at Bangalore’s Com DEALL Trust University and Nottingham Trent. from top to bottom. In other words, some people with autism may find it difficult to filter incoming information — this may be due to fundamental differences in brain structure like the one that Arlotta has seen in organoids.
After studying CHD8, Arlotta and her team developed two more organoids, this time focusing on two other genes associated with the condition: ARID1B and SUV420H1. Although these genes do different things, they have what Arlotta calls a “converging” effect on brain development — like CHD8, mutations in these genes also change the timing of cell development. cells in organoids, and affects the balance between excitatory and inhibitory neurons. “A lot of genes that ultimately cause disease can function in different ways: They converge not on the genes they use, but on the pathways they affect,” she said.
To further complicate matters, when Arlotta and her team altered the genetic landscape — introducing the same genetic mutations into stem cells from different donors — they found different effects. different effects on brain development. “Power is changed by context,” she says. “It’s really the whole genome that matters.”
Autism is a spectrum of different and overlapping traits, and this work confirms the suspicion that its genetic cause could also be a spectrum: different genes overlap in different and similar ways. interacts with the rest of an individual’s genetic profile to cause degrees and types of changes. Belmonte argues that a wide range of genetic variations produce a narrow range of changes in brain function, and that these changes continue to have many implications — and only by uncovering that convergence can we could get the answer, Belmonte argued. “If you try to define everything genetically, you are really getting into the roots, and if you look at the narrowly defined phenotypes, you are hacking into the branches,” he said.
Arlotta hopes working with organoids will help scientists build a better picture of the underlying processes of ASD and possibly begin to divide that spectrum into a smaller number of possible “groups”. provide information about treatments and therapies, or just help us better understand autism. . The three genes this study looked at all lead to changes to the balance of excitatory and inhibitory neurons, a breakthrough that could help pharmaceutical companies develop drugs that address this balance in extreme cases. “It is possible that some genes converge in one process and others,” says Arlotta. “But if we can reduce this super-complex condition to a few categories, that would be great for treatments.”
The study also demonstrates the value of organoids as a testing platform, says Arlotta. She describes them as “a new discovery site” for studying human brain development and says the study highlights the importance of time when neurons develop and connect. “Development is a symphony,” says Arlotta. “It was like going to a concert and suddenly the violins were out of tune with the other instruments. The music you get at the end is very different.”
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