How Genes Interfere with the Brain’s ‘Brakes’ in AutismNews
The Context: Scientists have identified hundreds of genes that could play a role in neurodevelopmental disorders like autism spectrum disorder (ASD), but how exactly these genes lead to brain dysfunction isn’t well understood.
The Study: Using 3D models of brain tissue made from stem cells called ‘assembloids’ and CRISPR gene editing technology, researchers have identified how specific genes affect brain cells called ‘interneurons’ during development, perhaps contributing to disorders like ASD. The study, published in Nature, was led by NYSCF – Robertson Stem Cell Investigator Sergiu Pasca, MD, of Stanford Medicine.
The Importance: This study establishes a new, more comprehensive model for studying developmental disorders of the brain, and could lead to better strategies for diagnosis and treatment.
Discovering how our genetics drive brain disorders is a hot topic, as it could help researchers develop targeted treatments, with perhaps a few genes contributing to multiple diseases.
“A cluster of gene defects that all produce a similar physiological deficit might be amenable to a single type of treatment,” Dr. Pasca told Stanford Medicine.
“The challenge now is to figure out what [these genes are] actually doing, how disruptions in them are actually causing disease,” he added to NPR. “And that has been really difficult.
Scientists can’t exactly run invasive genetic experiments on people, and mouse brains can only tell us so much. This is why Dr. Pasca’s team has been using assembloids – 3D aggregates of human brain tissue made from stem cells – to study how the actual human brain cells impacted in disease develop and interact.
Tracking an Interneuron’s Journey
For this study, the team was interested in exploring how a certain type of brain cell called ‘interneurons’ complete their pilgrimage across the brain during development, as this cell type has been implicated in ASD. Interneurons are inhibitory, meaning they calm brain signaling to keep it from firing out of control – the basis of diseases like epilepsy, and a phenomenon thought to play a role in ASD as well.
Interneurons’ journey begins in a part of the brain called the subpallium, where they are born. They then migrate to the cerebral cortex (the brain region associated with higher-level processes like language, memory, and reasoning).
“Interneurons are born in deep regions of the brain, and then they have to migrate all the way to the cortex. So now you can imagine that during that migration a lot of things could go awry,” remarked Dr. Pasca.
The scientists created organoids – clumps of brain cells made from stem cells – that modeled each of these two brain regions, and then put them next to each other, where they fused to become assembloids. This way, the team could watch the migration happen in a dish in real time.
Narrowing Down Genes
The scientists wanted to use their model to take a closer look at genes suspected to be implicated in interneuron migration and/or function. The list of suspects is a long one: 425 genes to be exact.
Luckily, the revolutionary gene editing tool CRISPR gave researchers the ability to make such alterations in interneurons and then track their journey to see which genes were causing problems.
“About 10% [of the genes] are actually interfering either with the generation of these interneurons of the cerebral cortex or with their migration,” reported Dr. Pasca.
And without interneurons available to pump the brakes, cells are prone to overfiring, like an electrical storm in the brain.
Many of these genes have not been implicated in neurodevelopmental disorders before, but several were the usual suspects scientists have known to be involved – a promising validation of the team’s experimental model.
“This was a comfort factor,” said Dr. Pasca. “It meant we weren’t insane — this approach works.”
Researchers across the field, such as NYSCF – Robertson Stem Cell Investigator Alumna Kristen Brennand, PhD, of Yale University are optimistic about what an approach like this could mean for the future of neurodevelopmental diseases.
“This improved genetic understanding will let us do better at diagnosing patients, I hope, but also treating them, because we’ll know which pathways we can target to intervene.
Read more in The Washington Post
Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
Xiangling Meng, David Yao, Kent Imaizumi, Xiaoyu Chen, Kevin W. Kelley, Noah Reis, Mayuri Vijay Thete, Arpana Arjun McKinney, Shravanti Kulkarni, Georgia Panagiotakos, Michael C. Bassik & Sergiu P. Pașca. 2023. Nature. DOI: https://doi.org/10.1038/s41586-023-06564-w
Cover image: Forebrain assembloids: The human migrating interneurons are in green; nuclei are in pink.
Credit: Pasca lab