Roadmap of Brain Development Offers Insight into Autism and Schizophrenia

The Context: Studying brain development can be difficult since scientists cannot easily access developing brain tissue. Creating models of human brain development from stem cells allows researchers insight into exactly how neurodevelopment occurs and goes awry in conditions like autism, schizophrenia, intellectual disability, ADHD, Down syndrome, and others.

The Study: A study in Science by NYSCF – Robertson Neuroscience Investigator Sergiu Pasca, MD, of Stanford University uses stem-cell-based models called ‘organoids’ to mimic longer term brain development and track how genes (including autism spectrum disorder (ASD) and schizophrenia-associated genes) are switched on and off during the process.

The Importance: The results reveal how different disease risk genes affect different populations of brain cells during development. This study also creates a ‘roadmap’ for brain development that helps scientists understand which genes influence which cells at which times.

Many neurological diseases have genetic components that influence the way the brain develops. However, studying the interplay between genes and brain development isn’t easy: scientists can’t reach inside a developing brain to see what’s happening, and mouse studies can only model very early stages of the process.

“We know a bit about the early stages because [the situation is] very similar to what happens in rodents,” NYSCF – Robertson Neuroscience Investigator Sergiu Pasca, MD, of Stanford University tells Scientific American. “But everything beyond the second trimester [of pregnancy] and soon after birth is poorly understood.”

A new study in Science by Dr. Pasca’s team uses stem-cell-based models called ‘organoids’ to mimic longer-term brain development and track the influence of autism spectrum disorder (ASD) and schizophrenia-associated genes on the process. The results reveal how genes are switched on and off to affect different populations of brain cells during development.

What Are Organoids?

Organoids are clusters of human brain cells made from stem cells. They model cell interactions and development — mimicking what takes place in the human body and allowing scientists to study the dynamics of brain development in unprecedented detail.

Although organoids do not carry all cell types and components of the brain, they still allow scientists to follow how many key brain cell types are created during development.

“There’s no vasculature, sensory input or microglia—the brain’s immune-surveillance cells, which are derived outside the brain,” explains Dr. Pasca. “Despite this, we find there’s an intrinsic program: cells know what specific cell type to become and when.”

Creating a Better Model of Brain Development

Dr. Pasca’s team created organoids specific to either the frontal or rear regions of the forebrain (the structure associated with higher cognitive processes). As these organoids matured, they formed different types of neurons as well as glia (support cells).

Then, using DNA sequencing, the researchers charted gene regulation as the brain cells developed over 20 months, a period that captures prenatal and postnatal development. Excitingly, this information is now available online as a resource for the wider research community.

“The work brings new understanding of how, as the brain is formed, distinct regulatory regions of the genome are used to execute specific tasks—for example, the generation of specific types of neurons,” says NYSCF – Robertson Stem Cell Investigator Alumna Dr. Paola Arlotta of Harvard University. “There’s so much new information here to guide years of work aimed at decoding the mechanisms that form the human brain.”

Autism, Schizophrenia, and the Developing Brain

Dr. Pasca’s team then turned their attention to genes linked to ASD and schizophrenia. The scientists found that many autism risk genes appeared active in progenitor cells (cells present in very early development), while schizophrenia risk genes came into play later on, affecting glia and inhibitory neurons.

“Some of these processes are going awry early in development, but the timing is different for autism and schizophrenia,” says Dr. Pasca. “A stronger, earlier genetic insult [such as a mutation] to the developing brain probably is associated with autism. A later one that’s a bit subtler but can have long-term consequences is associated with schizophrenia.”

Dr. Pasca is hopeful that creating a map of brain development will enable in-depth research into a multitude of diseases, telling researchers which stages a mutated gene might be perturbing.

“We first have to create this map of the developing brain but ultimately use it to understand disease, because that’s the promise,” he remarks.

Journal Article:

Chromatin accessibility dynamics in a model of human forebrain development
Alexandro E. Trevino, Nasa Sinnott-Armstrong, Jimena Andersen, Se-Jin Yoon, Nina Huber, Jonathan K. Pritchard, Howard Y. Chang, William J. Greenleaf, Sergiu P. Pașca. Science. 2020. DOI: 10.1126/science.aay1645

Photo credit: Pasca Lab, Stanford University