Researchers at the International Institute of Molecular Mechanisms and Machines (IMol) of the Polish Academy of Sciences have discovered a key mechanism behind sensory problems commonly associated with autism. A research team led by Dr. Justyna Zmorzynska studied how overactivity of cellular pathways that help control growth and brain signaling affects the brain’s ability to process light. They used zebrafish, a common research model, to examine a disease called tuberous sclerosis complex (TSC), a genetic disorder that often causes autism-like symptoms. The findings, published in iScience, provide new insights into how disruptions in brain signaling can lead to abnormal responses to sensory experiences, such as sensitivity to light, which are common in people with autism.
Tuberous sclerosis is a genetic disease that affects thousands of people worldwide. This occurs when certain genes that help regulate cell growth stop functioning properly. This causes overactivity of a specific cellular pathway called mechanistic target of rapamycin complex 1 (mTORC1). This hyperactivity can lead to a variety of problems, including seizures, learning difficulties, and autism-like behavior. “We know that when mTORC1 is overactive, it disrupts brain development and can lead to autism-like behaviors, but we wanted to understand how it affects sensory processing, specifically sensitivity to light,” explains Dr. Zmorzynska. “
Researchers used zebrafish with faulty genes associated with the tuberous sclerosis complex to explore how this overactive pathway interferes with brain function. They discovered that zebrafish respond abnormally to light. Normally, zebrafish prefer well-lit areas, but these TSC zebrafish did not show this preference, spending equal amounts of time in bright and dark environments. The researchers determined that the unusual behavior was not due to a developmental or vision problem in the fish. Instead, the problem lies in a part of the brain called the left dorsal habenula, which plays a key role in processing sensory information such as light.
To delve deeper, the team studied brain activity in zebrafish with tuberous sclerosis complex. They found that neurons in the left dorsal habenula were abnormally active and did not calm down as they normally would in response to repeated exposure to light. “Overactivity in this part of the brain, caused by overactivity of the mTORC1 pathway, may explain the sensory processing problems we observed in fish,” Dr. Zmorzynska elaborates.
An important finding of the study is that a drug called rapamycin can block the mTORC1 pathway, thereby restoring the normal light preference of TSC zebrafish. After treatment, brain activity in the left dorsal habenula of the zebrafish returned to normal levels, and they again showed a preference for light. This shows that overactivity of this pathway directly contributes to sensory processing problems in people with tuberous sclerosis, as well as those with autism.
These findings may have broader implications beyond the tuberous sclerosis complex, as overactivity of the mTORC1 pathway has also been implicated in other developmental disorders. “Our research brings hope for new treatments,” Dr. Zmorzynska said. “By targeting this specific pathway in the brain, we may be able to help people who struggle with sensory issues common in autism.”
However, researchers also caution against widespread use of drugs such as rapamycin in people with autism unless they demonstrate that the pathway is overactive. “While rapamycin works well in our zebrafish model, it can also cause adverse side effects in animals that do not have mTORC1 overactivity,” Dr. Zmorzynska warned. “It is important to ensure that treatments are targeted and only given to patients who truly need it.”
The study highlights the need for further research into how this brain pathway affects sensory issues in autism. Future work will aim to explore how mTORC1 affects other sensory processing functions and whether these findings can be applied to human clinical trials. Ultimately, the research provides a clearer understanding of how problems with brain signaling contribute to the sensory difficulties many people with autism face, opening up new possibilities for treatment.
Journal reference
Doszyn, O., Kedra, M., and Zmorzynska, J. “Hyperactive mechanistic target of rapamycin complex 1 disrupts habenula function and light preference in a zebrafish model of tuberous sclerosis.” iScience, 2024 .
About the author
Justina Zmosinska is a developmental neurobiologist and the head of the Laboratory of Developmental Neurobiology at the International Institute of Molecular Mechanisms and Machines (IMol) in Warsaw, Poland. She leads a group focused on neuropsychiatric disorders, specifically autism spectrum disorder and intellectual disability. Her research explores how early environmental factors, such as maternal infections during pregnancy, influence brain development and connectivity.
A key aspect of her work involves studying the role of the mTORC1 pathway in brain development and its association with neuropsychiatric disorders. In her research, she uses zebrafish models to study these developmental processes, providing insights into how brain connections are disrupted.
She graduated from the University of Warsaw with a Master’s degree in Molecular Biology and conducted a Master’s program at the Department of Medical Genetics, Institute of Maternal and Infant Research (Warsaw, Poland). She completed her PhD program at the Department of Genetics, University Medical Center Groningen, The Netherlands. She received the Jan Kornelius de Cock stichting doctoral scholarship for three consecutive years (2011-2013). She was a postdoctoral researcher and senior researcher at the Laboratory of Molecular and Cellular Neurobiology at the International Institute of Molecular and Cell Biology (PL) in Warsaw. She is teaching an internship. Didier Stainier’s laboratory (Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany) and Professor William Harris’s laboratory (Department of Physiology, Development and Neuroscience, Cambridge, UK). She has also received several prestigious grants, including an NCN SONATA BIS grant, which supported her research on the effects of maternal infections on brain development.
