Some of the symptoms of neurodevelopmental disorders (NDDs) such as autism spectrum disorder and epilepsy may result from dysfunction of certain neurons in the brain and their ability to change their properties in response to experiences—a process called experience-dependent plasticity. In preclinical research published in Nature , a team led by investigators at Mass General Brigham identified genes involved in these neurons’ plasticity and then demonstrated benefits to overexpressing one key gene.
“Cognitive impairment and seizures are hallmarks of neurodevelopmental disorders and represent a large, unmet clinical need,” said senior author Amar Sahay, PhD, of the Department of Psychiatry at Mass General Brigham and an associate member of the Broad Institute of MIT and Harvard. “We show in proof-of-concept studies that targeting one candidate gene could be sufficient to reverse developmental deficits, even in adulthood.”
The Sahay team, led by co-first authors Yu-Tzu Shih, PhD and Jason Alipio, PhD, screened for genes involved in the plasticity of a specific type of brain cell known as parvalbumin inhibitory neurons. The researchers chose to further pursue a gene, Meis2 , which they found is expressed at low levels in parvalbumin inhibitory neurons but is elevated in response to experience.
Using gene therapy, Sahay and colleagues found that boosting Meis2 expression in parvalbumin inhibitory neurons in a widely used NDD mouse model rebalanced excitation and inhibition in the brain, restored experience-dependent plasticity, and improved spatial and social memory. The same intervention also reduced seizure frequency and corrected abnormalities in brain network activity important for cognition, suggesting broad functional recovery.
“The development of new therapeutics for NDDs is dependent on understanding the mechanisms by which risk genes cause impairments,” said Sahay. “The path from mechanism to therapy is a long and arduous one, but starting with a deep insight into mechanism is crucial to increasing the likelihood of success.”
Authorship: In addition to Sahay, Mass General Brigham authors include Yu-Tzu Shih, Jason Bondoc Alipio, Nathaniel Green, Alok Nath Mohapatra, Travis D. Goode, Muthu Panchanatham, Devesh Pathak, Lai Ping Wong, and Ruslan Sadreyev. Additional authors include Zin-Juan Klaft, Jung Ho Hyun, Omar Ahmed, and Chris Dulla.
Disclosures: Sahay, Shih and Alipio are named co-inventors on patent filing related to this work.
Funding: This study was funded in part by the Simons Collaboration on Plasticity and the Aging Brain, National Institutes of Health (R01MH111729, R01MH131652, R01MH111729-04S1, R01AG076612, R01AG076612-S1 diversity supplement, R01NS139468, R01NS113499), James and Audrey Foster MGH Research Scholar Award, MGH Department of Psychiatry, MGH ECOR Fund for Medical Discovery Fundamental Research Fellowship Award, and Harvard Brain Initiative Travel Grant.
Paper cited: Shih YT et al. “Pro-cognitive restoration of experience-dependent parvalbumin inhibitory neuron plasticity in neurodevelopmental disorders” Nature DOI: 10.1038/s41586-026-10907-8
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Nature
Observational study
Animals
Pro-cognitive restoration of experience-dependent parvalbumin inhibitory neuron plasticity in neurodevelopmental disorders
12-Aug-2026