Hypersensitivity in autism manifests itself in a plethora of ways, from a distaste for certain textures to increased awareness of specific sounds. The study, published on March 2 in Nature Neuroscience, found that mice with knockout mutation of a gene called Shank3 showed characteristics of autism. Scientists identified a role of the cerebral cortex in mediating autism spectrum disorders, specifically finding that hypersensitivity was related to a deficit in inhibitory neuronal cells in this cortical region.
As for translational implications of this project for patients with autism spectrum disorder, there are “achievable and ambitious goals of which this particular study is a small part of,” said Christopher Deister, first co-author of the study and a postdoctoral research associate who works in the lab of Christopher Moore, associate director of the Carney Institute.
These goals include developing potential interventions, and obtaining a stronger understanding of the genetic and neural basis of autism in higher-level organisms and people. Guoping Feng, a co-senior author of the study who is affiliated with MIT, is particularly interested in pursuing these translational applications, according to Deister.
Feng designed the mouse models used in the study. Deister focused on normal sensory processing and fluency in running complex psychophysical experiments, such as analyzing the behavior of mice under certain conditions. Together, they were able to work toward understanding how hypersensitivity was mediated in the brain using an autism mouse model.
“We basically just got to work, because it seemed too perfect,” Deister said of their partnership.
This partnership began when both Deister and his counterparts at MIT became interested in “looking at abnormal sensory processing in autism models,” he said. The group particularly focused on the Shank3 mouse model, which Feng had previously developed as a model for autism spectrum disorders.
The researchers used two mouse models: one with a knockout of the Shank3 gene, and the other with a conditional knockout, which allowed researchers to knockout the Shank3 gene in a specific location of the brain at a specific time in development. By comparing experiments with both models, scientists were able to parse out where hypersensitivity associated with autism was impacted in the brain.
“We ended up doing what amounted to … six papers worth of work,” Deister said, adding that the study was published after roughly three years of experimentation and analysis. “There were so many genetic groups that had to be put together, we had to figure out the right ways of actually comparing all these things in a fair way.”
These comparisons eventually allowed them to recapitulate their findings in multiple experiments. “If you knockout Shank3 just in the somatosensory cortex, even in an adult animal, we get this autistic-like, hypersensitive sensory process,” Deister said, referencing how the researchers were able to determine that their mouse system was a good model for autism.
Scientists were then able to identify the specificity of where hypersensitivity was controlled in the brain, even further than the somatosensory region. They found that dysfunction of inhibitory, rather than excitatory cells, seemed to be mediating this response.
“Everyone has been studying this protein as if it’s part of the excitatory system,” Deister said, adding that their findings showed otherwise. “Excitation in the brain goes down, which is a little bit counterintuitive if you think these animals are processing information at a higher rate.”
According to Deister, each author on the paper has their own unique ideas for how to take this research to the next level. Feng is more focused on integrating the findings with work to create therapies for autistic patients, and Deister hopes to delve into the paradox of the neural circuit and the role of the inhibitory cells.
The study, Deister said, marked the beginning of “a lot of other possibilities.”