Brain organoids reveal genetic mutations affect emergence of neurons in people with autism

Mutations in three autism-associated genes have been shown to affect the pace at which certain types of neurons emerge in the developing brain.

Autism is partly influenced by genetic factors, although the contribution of genetics to the condition and the underlying mechanisms are still poorly understood. The findings by researchers at Harvard University and the Broad Institute (both in Cambridge, Massachusetts) are unique in showing that mutations in three distinct genes — ARID1B, CHD8 and SUV420H1 — have similar effects on the developing brain.

'Much effort in the field is dedicated to understanding whether commonalities exist among the many risk genes associated with autism' said Professor Paola Arlotta, the senior author of the study, published in the journal Nature. 'Our data show that multiple disease mutations indeed converge on affecting the same cells and developmental processes, but through distinct mechanisms. '

The development of the fetal brain is a complex and tightly controlled process, in which cells divide and gradually differentiate into different classes of neurons that make up the circuits of the brain. According to co-lead author of the study, Dr Martina Pigoni: 'If you have some cells forming too early or too late compared to when they are supposed to you might be changing the way circuits are ultimately wired'.

To study the effects of the mutations on development, the researchers used organoids derived from human stem cells. Brain organoids, clusters of human cells grown in a laboratory, are able to model the way that neurons emerge in the early human brain, particularly in the cortex.

By studying the RNA and protein markers of different types of neurons in the organoids, the group found that each mutation had similar effects on the timing of the development of two types of neurons. One type appeared earlier than usual for all the mutations, whereas another was delayed. Studying the activity of the neuronal network in the organoids also suggested that the wiring of neural circuits was altered.

The group then looked at brain organoids derived from the stem cells of patients with the mutations, where they observed the same effects on development. However, the degree to which the genetic mutations affected the timing of the development of the different types of neurons varied among the stem cell donors.

Autism is notoriously difficult to study, due to the wide variety of genes and environmental factors that can influence the condition. Research into the genetics of autism has also proved controversial (see BioNews 1113).

'It is puzzling how the same autism risk gene mutations often show variable clinical manifestations in patients' said Professor Arlotta. 'We found that different human genomic context can modulate the manifestation of disease phenotypes in organoids, suggesting that we may be able to use organoids in the future to disentangle these distinct genetic contributions'.