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 of 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.

Their discovery could help to explain symptoms experienced by some individuals with ASD 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 while she was working 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 brain neurons of mouse models of ASD. But they found these changes had no effect of touch-related behaviors.

When the researchers altered ASD-related genes in the peripheral sensory neurons of the mouse models, the mice became more sensitive to touch. If the gene alterations were then corrected, 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 says.

“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 in the sensory neurons differed among the individual genetic models of ASD. But all of the mice responded positively to treatment with drugs that modulate GABA_A receptors.

GABA_A receptors essentially act as the “gates” on each neuron to control the level of information transmitted from the PSNs to the spinal cord and the brain. Tamping down these receptors may reduce the intensity of the signals that the neurons are transmitting to the brain and spinal cord.

Orefice notes that the treatments did not improve all of ASD-related symptoms experienced by the mouse models, 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 GABA_A receptor modulators (such as benzodiazepams) 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 GABA_A receptors but does not cross the blood-brain barrier, but the compound is not FDA approved and has not been tested in humans.

What’s Next

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.”

About the Mass General Research Institute
Research at Massachusetts General Hospital is interwoven through more than 30 different departments, centers and institutes. Our research includes fundamental, lab-based science; clinical trials to test new drugs, devices and diagnostic tools; and community and population-based research to improve health outcomes across populations and eliminate disparities in care.
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