Brain organoids offer a window into autism

Overview: Researchers investigating the effects of genetic abnormalities associated with autism and human brain development found that brain organoids engineered to have low levels of the ASD-associated SHANK3 gene were associated with increased neuronal firing and adhesion of cells to each other. found to have distinct features such as route confusion. A sign of ineffective neurotransmission.

sauce: University of Utah

Whatever you do, don’t call them “minibrains,” says health scientists at the University of Utah. It provides insight into the brain and reveals differences that may contribute to autism in some people.

“Previously, we thought it was too difficult to model the organization of cells in the brain,” says Alex Shcheglovitov, PhD, assistant professor of neurobiology at the U of Health. “But these organoids self-assemble. Within months, we see layers of cells reminiscent of the cerebral cortex in the human brain.”

Studies describing organoids and their potential for understanding neurological diseases include: Nature Communications October 6th We have Shcheglovitov as Senior Author and Dr. Yueqi Wang (former graduate student in his lab) as Lead Author. They conducted the study with Dr. Simone Chiora, a postdoctoral scientist at the University of Utah, Harvard, University of Milan, and Montana State University, and other collaborators.

autism research

Having the ability to model aspects of the brain in this way gives scientists a glimpse into the inner workings of living organs that would otherwise be nearly impossible to access. Also, because organoids grow in dishes, they can be ly tested in ways that the brain cannot.

Shcheglovitov’s team used an innovative process to investigate the effects of genetic abnormalities associated with autism spectrum disorders and human brain development. They found that organoids engineered to have lower levels of genes SHNK3had distinct characteristics.

The autism organoid model looked normal, but some cells didn’t work properly:

• neurons become hyperactive and fire more frequently in response to stimuli,
• Other signs indicate that neurons may not be efficiently passing signals to other neurons.
• A specific molecular pathway that allows cells to adhere to each other has been disrupted.

These findings help shed light on the cellular and molecular causes of autism-related symptoms, the authors say. They also show that organoids grown in the laboratory are valuable for improving our understanding of the brain, how it develops, and what can go wrong during disease.

“One goal is to use brain organoids to test drugs or other interventions to reverse or treat the disorder,” said co-author of the study and assistant professor of biomedical engineering in the United States. Dr. Jan Kubanek said:

Building better brain models

Scientists have long sought a suitable model for the human brain. Although laboratory-grown organoids are not new, previous versions did not develop them in a reproducible manner, which made interpretation of the experiments difficult.

To create an improved model, Shcheglovitov’s team took cues from how the brain normally develops. Researchers inspired human stem cells to become neuroepithelial cells. Neuroepithelial cells are a specific stem cell type that form self-organizing structures called neural rosettes in the dish. Over the course of several months, these structures coalesced into spheres, increasing in size and complexity at a rate similar to the development of the developing fetal brain.

After five months in the lab, the organoids were reminiscent of “one wrinkle in the human brain” 15 to 19 weeks after conception, says Shcheglovitov. This structure contained a series of neurons and other cell types found in the cerebral cortex, the outermost layer of the brain involved in language, emotion, reasoning, and other high-level mental processes.

Like human embryos, organoids self-organize in predictable ways, forming neural networks that pulse in oscillating electrical rhythms and generate diverse electrical signals characteristic of different types of mature brain cells. Did.

“These organoids had a pattern of electrophysiological activity that resembled the actual activity in the brain, which I didn’t expect,” says Kubanek. “This new approach models most major cell types in a functionally meaningful way.”

Shcheglovitov says that these organoids, which more reliably reflect the complex structure of the cortex, will allow scientists to study how specific types of cells in the brain develop and work together to perform more complex functions. It explains that it can be done.

“We are beginning to understand how the complex neural structures of the human brain arise from simple progenitor cells,” says Wang. “And his 3D organoids, derived from stem cells containing genetic mutations, can be used to measure disease-related phenotypes.”

He adds that using organoids will allow researchers to better investigate what happens in the early stages of neurological conditions, before symptoms appear.

Funding: Support for this work was provided by the National Institutes of Health, Brain Research Foundation, Brain Behavior Research Foundation, Whitehall Foundation, University of Utah Neuroscience Initiative, and University of Utah Genome Project Initiative.

See also

About this Autism Research News

author: Julie Pine
sauce: University of Utah
contact: Julie Kiefer – University of Utah
image: Image credited to Yueqi Wang

Original research: open access.
“Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from a single neural rosetteBy Alex Sheglobitov et al. Nature Communications

Overview

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

The human telencephalon is an evolutionarily evolved brain structure that is associated with many human-specific behaviors and disorders. However, the cell lineages and molecular pathways involved in human telencephalon development remain largely unknown.

We generate human telencephalic organoids from stem cell-derived single neural rosettes to investigate telencephalic development under normal and pathological conditions.

Single neural rosette-derived organoids have been shown to contain not only macroglia and endothelial cells, but also palatal and subpalatal neural progenitors, excitatory and inhibitory neurons, and exhibit predictable organization and cytoarchitecture. It has been.

We comprehensively characterize the neuronal properties of SNR-derived organoids and identify transcriptional programs associated with specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development.

Also organoid neurons with hemizygous deletions of genes associated with autism and intellectual disability SHNK3 We show intrinsic and excitatory synaptic defects and impaired expression of several clustered protocadherins.

Collectively, this study validates SNR-derived organoids as a reliable model to study human telencephalic corticostriatal development, demonstrating intrinsic, synaptic, and clustered protocadherin expression in human telencephalic tissue. identify defects SHNK3 Hemizygosity.