Evidence continues to mount that some and perhaps many of the biological abnormalities that underlie autism spectrum disorder (ASD) begin well before birth, as the brain’s cerebral cortex is developing. It’s still not known, however, when and where in the emerging brain these irregularities first manifest.

These questions are addressed in a study published in the February issue of Nature Neuroscience. Researchers led by 2018 BBRF Young Investigator Simon T. Schafer, Ph.D. and 2013 BBRF Distinguished Investigator and Scientific Council member Fred H. Gage, Ph.D., both of the Salk Institute for Biological Studies, show that some autism-related abnormalities in neural cells are traceable to a time when they were still stem cells—that is, a time before they became neurons.

All of the mature brain’s neurons and support cells (such as astrocytes and glial cells) begin their existence as neural stem cells (NSCs). Obviously, these cells cannot be “sampled” from living people, including those diagnosed with autism. But in recent years, a technology has emerged that enables scientists to take skin cells from people and reprogram them to re-develop, in a culture dish, as cells of different types. This enables them, for example, to watch neurons develop from NSC precursors—and to do so with cells bearing the genetic variations carried by patients.

Prior experiments of this kind in ASD indicated that abnormalities in patients’ neural cells, caused by genetic variations, impaired the cells’ ability to communicate properly with one another. The new research found aberrations in ASD patients’ reprogrammed cells that occur very early, in the stem-cell phase.

The team analyzed patterns of gene activation in patient-derived NSCs and the neurons they give rise to. They also studied physical properties of these cells, and compared them with cells grown from people who do not have ASD. They found that NSCs derived from patients were genetically “primed” to activate specific sets of genes in abnormal ways. These abnormalities, in turn, caused emerging neurons to mature more rapidly than normal, among other differences.

“Our analysis suggests that some ASD-associated changes are likely the consequence of pathological events triggered during NSC stages early in development,” the team said. "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," said Dr. Gage, the study's senior author and president of the Salk Institute.