PHILADELPHA— A new study from Penn Medicine lends further evidence that the social behaviors tied to autism spectrum disorders (ASD) emerge from abnormal function of sensory neurons outside the brain. It’s an important finding, published today in the journal Cell Reports, because peripheral sensory systems—which determine how we perceive the environment around us —makes for more accessible therapeutic targets to treat ASD-related symptoms, rather than the central brain itself.
In the fruit fly Drosophila— a powerful model for studying neurobiology— the researchers showed that loss of a protein known as neurofibromin 1 caused adult male flies to have social impairments. Those deficits, the researchers also showed, traced back to a primary disruption in a small group of peripheral neurons controlling external stimuli, like smell and touch, that communicate to the brain.
“These data raise the exciting possibility that the root of the problem doesn’t begin with errors in the brain itself. It’s the disrupted flow of information from the periphery to the brain we should be taking a closer look at,” said senior author Matthew Kayser, MD, PhD, an assistant professor in the department of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania. “The findings should help guide the field toward sensory processing therapeutic targets that, if effective, could be transformative for patients suffering from these disorders.”
In humans, a loss of neurofibromin 1 is associated with neurofibromatosis type 1 (NF1), a neurodevelopmental disorder with high rates of ASD, but how that loss leads to social deficits is unknown. Past studies have also shown a link between the peripheral sensory system and social deficits; however, this is the first study to implicate neurofibromin’s function.
Up to 50 percent of children with NF1 fall on the autism spectrum, and are 13 times more likely to exhibit highly elevated ASD symptoms, including social and communicative disabilities, increased isolation and bullying, difficulties on social tasks, and sensitivities to sound or light. Those symptoms are all tied to difficulties with processing sensory information. Face and gaze processing, for example, makes a social gesture like eye contact exceedingly difficult.
The team, led by Penn postdoctoral scientist Emilia Moscato, PhD, used genetically manipulated flies to show that a loss of neurofibromin led to diminished social courtship behavior and errors in gustatory sensory neurons called ppk23, which are known to coordinate such behaviors. These behavioral deficits stem from an ongoing role for neurofibromin in coordinating social functions in adults, as opposed to guiding development of social behavioral neural circuits.
More specifically, in vivo monitoring of neural activity in the mutant flies showed decreased sensory neuron activation in response to specific pheromonal cues, which then disrupted proper function of downstream brain neurons that direct social decisions. The disruption also led to persistent changes in behavior of the flies beyond the social interaction itself, suggesting a brief sensory error can have long-lasting consequences on behavior.
Next, the researchers aim to better understand how this mutation translates to disruption in brain activity and ultimately behaviors associated with ASD and NF1. They also hope to test different drugs in animal models to identify novel compounds that can restore social behaviors.
“Sensory processing is a readily testable entry-point into social behavioral dysfunction,” Kayser said, “so findings from these experiments have potential to rapidly impact the clinical setting.”
Co-authors of the study include Penn’s Moscato and Christine Dubowy, as well as James A. Walker of Massachusetts General Hospital.
This work was supported by a McMorris Autism Early Intervention Initiative Fund Pilot Study Award, a Burroughs Wellcome Career Award for Medical Scientists, a National Institutes of Health grant (DP2 NS111996), and an NIH New Program Development Award of the Intellectual and Developmental Disabilities Research Center at Children’s Hospital of Philadelphia/Penn (U54 HD086984).
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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.6 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.
Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.
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