Early development of autism exposed
Immunofluorescence image: 2D culture of subject-derived cortical neurons stained for neuronal markers MAP2 (red) and Tuj1 (green). [Salk Institute]
Salk Institute researchers have uncovered key differences in the patterns and speed of development of stem cells in individuals with, and without, autism spectrum disorder.
A stunning confocal microscopy image shows a 2D culture of the cortical neurons derived from an individual with ASD.
The image forms part of crucial research from Professor Rusty Gage, president of the Institute, and colleagues, who compared developing neural stem cells created from individuals with ASD to those without the developmental disorder.
The researchers hope the latest results could lead to diagnostic methods to detect ASD at an early stage, when preventive interventions could potentially take place.
"Although our work only examined cells in cultures, it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD," says Gage. "We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders."
For the study, the researchers took skin cells from eight people with ASD and five people without ASD and turned them into pluripotent stem cells; cells that have the ability to develop into any cell type.
They then coaxed the stem cells to develop along the path of becoming neurons by exposing them to certain chemical factors.
By using molecular "snapshots" from different developmental stages in the stem cells, Gage and colleagues tracked the genetic programs that switched on in a certain order as the stem cells developed into neurons.
Image data were captured and processed using a Zeiss LSM780 confocal microscope system and a Zeiss CSU Spinning Disk Confocal Microscope, equipped with a Yokogawa spinning disc scan head with an EM-CCD camera.
Tiled image stacks were processed using ZEN Imaging software, from Carl Zeiss Microscopy.
Analyses revealed key differences in the cells derived from people with ASD.
For instance, the researchers observed that the genetic program associated with the neural stem-cell stage turned on earlier in the ASD cells than it did in the cells from those without ASD.
This genetic program includes many genes that have been associated with higher chances of ASD.
In addition, the neurons that eventually developed from the people with ASD grew faster and had more complex branches than those from the control group.
"It's currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred," says Simon Schafer, a postdoctoral fellow in the Gage lab.
"A major challenge in the field has been to determine the critical developmental periods and their associated cellular states," he adds. "This research could provide a basis for discovering the common pathological traits that emerge during ASD development."
"This is a very exciting finding, and it encourages us to further refine our methodological framework to help advance our understanding of the early cell biological events that precede the onset of symptoms," says Gage. "Studying system dynamics could maximize our chance of capturing relevant mechanistic disease states."
The researchers say the experiments in this study will lead to more dynamic approaches for studying the mechanisms that are involved in ASD predisposition and progression.
They next plan to focus on the creation of brain organoids, 3D models of brain development in a dish that enable scientists to study the interactions between different types of brain cells.
Research is published in Nature Neuroscience.