The findings lay the groundwork for identifying new diagnostics and exploring potential treatments, according to Dr. Paola Arlotta of Harvard University in Cambridge and colleagues.
"When we saw that, one after the other, each of these genes affected the same cell types and a similar developmental process, we (had) a eureka moment!" Dr. Arlotta told Reuters Health by email.
"Our finding that different autism-risk genes converge on a phenotype of asynchronous neuronal development, but mostly diverge at the level of molecular targets, suggests that a shared clinical pathology of these genes may derive from higher-order processes of neuronal differentiation and circuit wiring," she said.
Further, she added, "These results encourage future investigation of therapeutic approaches aimed at the modulation of shared dysfunctional circuit properties, in addition to shared molecular pathways."
As reported in Nature, Dr. Arlotta and colleagues generated organoid models of the cerebral cortex, each with mutations in one of three ASD risk genes: SUV420H1, ARID1B, and CHD8.
The team investigated the effects of the mutations in multiple cell lines from different ASD donors using several technologies, including single-cell RNA sequencing and single-cell ATAC-sequencing to measure changes and gene expression; proteomics to measure responses in proteins; and calcium imaging to see whether molecular changes were reflected in abnormal activity of neurons and their networks.
Each mutation showed asynchronous development (acceleration or deceleration) of two cortical neuronal lineages, GABAergic inhibitory neurons and deep-layer excitatory projection neurons; however, as noted by Dr. Arlotta, although similar neurons were affected, each mutation acted through a different molecular pathway.
Comparisons among organoids made from different donors showed that while the overall changes were similar, the level of severity varied across individuals. This means that the risk genes' expressivity is influenced at the molecular level by the genomic context of each individual, dependent on both the risk gene and the developmental defect.
Calcium imaging of the organoids showed that these early-stage developmental changes are followed by abnormal circuit activity.
Dr. Arlotta added, "One exciting journey will be that of generating organoids that carry mutations in large numbers of ASD-risk genes. Screening across a large panel of genes will be very informative to understand whether the convergence of defects spans across many more genes."
"We are also excited to explore whether early developmental abnormalities ultimately affect the properties and functions of neural circuits," she said. "These initial results (showing) that the activity of circuits in organoids is indeed affected by ASD mutations support further exploration. Circuits could, in principle, be manipulated in the therapeutic space."
Dr. Madeline Lancaster of the MRC Laboratory of Molecular Biology in Cambridge, UK, commented on the study in an email to Reuters Health, "The findings are very promising, and help add a piece to the puzzle of how autism may be arising already during early development."
"There has been a prevailing theory in the field that patients with autism may exhibit an imbalance in excitatory versus inhibitory neuronal activity," she said. "This study supports such an idea and points to differences in the production of those excitatory and inhibitory neurons."
Nonetheless, she added, "much more work will be needed to take this to potential treatments. I think the immediate next step will be to see how we can use this information to identify autism as early as possible."
"There is already good evidence that early intervention can alleviate some of the difficulties associated with autism, and so if these findings can provide new markers of the disorder even before obvious behavioral or cognitive difficulties, then that would make a big impact," Dr. Lancaster concluded.
SOURCE: https://go.nature.com/34K8O8x Nature, online February 2, 2022.
By Marilynn Larkin
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