At any given time, your brain receives thousands of signals from the peripheral sensory neurons (PSNs) that transmit information from your skin and organs.
You typically aren’t aware of most these signals because your nervous system is good at separating the ones that need to be brought to your attention—the pain of touching a hot surface, for example—from those that can be safely processed in the background.
But what happens if the volume on all these signals is turned up? The sensations could quickly become overwhelming. A breeze or a gentle hug could turn into an unpleasant or even painful touch.
In studies of mouse models for autism spectrum disorder (ASD) at Harvard Medical School, Lauren Orefice, PhD (now an Assistant Investigator in the Mass General Department of Molecular Biology), David Ginty, PhD, and their team found that a similar process of peripheral nerve dysfunction occurs in some genetic forms of ASD, which could explain symptoms such as touch overreactivity, anxiety and social impairment.
The findings add an intriguing new perspective to our understanding of ASD, which was long thought to be solely a disorder of the brain. They could also lead to new treatment strategies to reduce the burden of these symptoms on ASD patients and shed light on how sensory input influences brain development.
A Series of Surprising Findings
Orefice was recently named the grand prize winner of the Eppendorf & Science Prize for Neurobiology for this work, which she is now continuing at Mass General.
In a recent interview, she explained that the findings originated from a question that arose when she was a postdoc in the Ginty Lab. “We were struck by the observation that some people with ASD often had abnormal responses to light touch,” she says. “But nobody really understood how or why this was occurring.”
The team started by investigating the effects of altering gene function in the neurons within the brains of the ASD mouse models, but found these changes had no effect on touch-related behaviors.
Surprisingly, it was altering ASD-related gene function only in the peripheral sensory neurons (PSNs) that led to abnormal touch behaviors in the mice.
The researchers then tried correcting the gene function only in the PSNs of the mice models and found that the symptoms of touch overreactivity improved.
“What was even more surprising was that if the mice had dysfunction in their PSNs during early development, this also led to abnormal brain development and the genesis of some other ASD-like behaviors,” Orefice said.
“It tells us normal touch input is needed during development to have correct wiring of these brain circuits and how the sense of touch is important for brain development and behavior.”
A Deeper Dive Offers More Clues
Further investigation found the mechanisms by which ASD-associated gene mutations cause this overreactivity differed among the individual genetic models, but all of the mice responded positively to treatment using drugs that that modulate GABAA receptors.
GABAA receptors essentially act as the “gates” on each neuron that control the level of information transmitted from the PSNs to the spinal cord and the brain.
Orefice notes that treating touch overreactivity does not improve all ASD-related symptoms in the mice, such as memory impairments, motor dysfunction and shortened life span.
“Touch is not the only issue in autism and peripheral sensory neurons are not the only area of dysfunction.”
The Pathway To New Treatments
While these findings are encouraging, there’s a long road ahead before they can be translated into treatments, Orefice says.
All FDA-approved GABAA receptor modulators cross through the blood-brain barrier and cause cognitive side effects such as sleepiness and difficulty thinking, so they are not ideal for long-term treatment, particularly in young children.
The team has identified a promising compound that acts on GABAA receptors but does not cross the blood-brain barrier. The catch is the compound is not FDA-approved and has not been tested in humans. Rigorous safety and efficacy testing will have to be done before it can be translated into a treatment.
Orefice and her team are now collaborating with clinicians to identify which ASD patients would benefit most from this treatment approach. They are also working to find biomarkers that can be used to measure the effectiveness of potential treatments and to gather data for first-in-human clinical trials.
“I’m hopeful we can expand our work with clinicians at Mass General and we are really thankful for the opportunities and access to patients and samples we have here,” she says.
“The Department of Molecular Biology at Mass General has been profoundly supportive in helping us set up the lab and allowing us to dream as big as we can,” she adds.
“They provide an environment where my lab can ask big, bold questions and support us in trying to understand the sense of touch and what it does.”
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