Insight into Autism from Brain Organoids Grown in a Dish

Introduction

Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes.

Whatever you do, don't call them "mini-brains," say University of Utah Health scientists. Regardless, the seed-sized organoids-which are grown in the lab from human cells-provide insights into the brain and uncover differences that may contribute to autism in some people.

Main Digest

"We used to think it would be too difficult to model the organization of cells in the brain," says Alex Shcheglovitov, Ph.D., assistant professor of neurobiology at U of U Health. "But these organoids self-organize. Within a few months, we see layers of cells that are reminiscent of the cerebral cortex in the human brain."

The research describing the organoids and their potential for understanding neural diseases publishes in Nature Communications on Oct 6th, 2022, with Shcheglovitov as senior author and Yueqi Wang, Ph.D., a former graduate student in his lab, as lead author. They conducted the research with postdoctoral scientist Simone Chiola, Ph.D., and other collaborators at the University of Utah, Harvard University, University of Milan, and Montana State University.

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Investigating Autism

The ability to model aspects of the brain in this way gives scientists a glimpse into the inner workings of a living organ that is otherwise nearly impossible to access. And since the organoids grow in a dish, they can be tested experimentally in ways that a brain cannot.

Shcheglovitov's team used an innovative process to investigate the effects of a genetic abnormality associated with autism spectrum disorder and human brain development. They found that organoids engineered to have lower levels of the gene, called SHANK3, had distinct features.

Even though the autism organoid model appeared normal, some cells did not function properly:

• Neurons were hyperactive, firing more often in response to stimuli.
• Other signs indicated neurons might not efficiently pass along signals to other neurons.
• Specific molecular pathways that cause cells to adhere to one another were disrupted.

These findings are helping to uncover the cellular and molecular causes of symptoms associated with autism, the authors say. They also demonstrate that the lab-grown organoids will be valuable for better understanding the brain, how it develops, and what goes wrong during disease.

"One goal is to use brain organoids to test drugs or other interventions to reverse or treat disorders," says Jan Kubanek, Ph.D., a co-author on the study and an assistant professor of biomedical engineering at the U.

Building a Better Brain Model

Scientists have long searched for suitable models for the human brain. Lab-grown organoids are not new, but previous versions did not develop in a reproducible way, making experiments difficult to interpret.

To create an improved model, Shcheglovitov's team took cues from how the brain develops normally. The researchers prompted human stem cells to become neuroepithelial cells in a dish, a specific stem cell type that forms self-organized structures called neural rosettes. Over months, these structures coalesced into spheres and increased in size and complexity at a rate similar to the developing brain in a growing fetus.

After five months in the lab, the organoids were reminiscent of "one wrinkle of a human brain" at 15 to 19 weeks post-conception, Shcheglovitov says. The structures contained an array of neural and other cell types found in the cerebral cortex, the brain's outermost layer involved in language, emotion, reasoning, and other high-level mental processes.

Like a human embryo, organoids self-organized predictably, forming neural networks that pulsated with oscillatory electrical rhythms and generated mixed electrical signals characteristic of various kinds of mature brain cells.

"These organoids had patterns of electrophysiological activity that resembled actual activity in the brain. I didn't expect that," Kubanek says. "This new approach models most major cell types and in functionally meaningful ways."

Shcheglovitov explains that these organoids, which more reliably reflect intricate structures in the cortex, will allow scientists to study how specific types of cells in the brain arise and work together to perform more complex functions.

"We're beginning to understand how complex neural structures in the human brain arise from simple progenitors," Wang says. "We can measure disease-related phenotypes using 3D organoids derived from stem cells containing genetic mutations."

He adds that by using the organoids, researchers can better investigate what happens at the earliest stages of neurological conditions before symptoms develop.

Related Information

• Reversing Effects of Autism Linked Mutation in Brain Organoids
• Organoids: Fitting a Mini Brain with a Tiny Cap

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This peer reviewed publication was selected for publishing by the editors of Disabled World due to its significant relevance to the disability community. Originally authored by University of Utah, and published on 2022/10/08 (Edit Update: 2023/01/04), the content may have been edited for style, clarity, or brevity. For further details or clarifications, University of Utah can be contacted at utah.edu. NOTE: Disabled World does not provide any warranties or endorsements related to this article.

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