Aug 13, 2026 —
A new study published in Nature reports that restoring activity of the transcription factor Meis2 in adult brain inhibitory neurons may reverse key neurological deficits in a mouse model of neurodevelopmental disorders.
The study, led by researchers at Mass General Brigham, identified Meis2 as a molecular regulator of experience-dependent plasticity in parvalbumin-positive, or PV, inhibitory neurons. These neurons play a central role in maintaining excitation-inhibition balance, supporting memory-related network activity, and regulating critical periods of brain plasticity.
In neurodevelopmental disorders such as autism spectrum disorder, epilepsy, and schizophrenia, PV neuron function and plasticity are frequently disrupted. The study suggests that Meis2 may act as an upstream regulator of a broader gene-expression program needed for PV neurons to respond to experience.
To test whether Meis2 restoration could reverse established deficits, the researchers used an AAV-based gene therapy approach to overexpress Meis2 in PV neurons within the hippocampal CA3/CA2 region of adult mice carrying a validated neurodevelopmental disorder risk model.
The intervention produced broad functional improvements. Spatial memory improved, social memory improved, seizure frequency declined, and abnormal oscillatory brain network activity, including gamma-frequency activity associated with PV neuron function, was normalized.
The findings are notable because the intervention was performed in adult mice, after the typical developmental windows of brain plasticity had already closed. This challenges the assumption that neurodevelopmental disorder-related circuit deficits must be corrected only during early development.
Mechanistically, Meis2 appears to regulate a downstream network of genes linked to PV neuron plasticity. Many genes in this pathway are associated with haploinsufficiency in autism spectrum disorder, epilepsy, and schizophrenia, suggesting that diverse genetic causes of neurodevelopmental disorders may converge on a shared PV neuron plasticity pathway.
The study remains preclinical, and significant questions remain before human translation. Future work will need to evaluate durability, safety, delivery strategy, dosing, and whether the approach can be extended beyond hippocampal PV neurons to additional brain regions relevant to social, sensory, and cognitive symptoms.
The findings position Meis2 as a potential therapeutic target for restoring adult brain plasticity in neurodevelopmental disorders and highlight AAV-mediated gene delivery as a proof-of-concept tool for modulating disease-relevant neuronal circuits.
