Meis2 gene identified as potential therapeutic target for neurodevelopmental disorders

Researchers at Mass General Brigham have identified a gene that may help restore impaired brain plasticity and reduce seizures in a mouse model of neurodevelopmental disorders (NDDs), pointing to a potential new therapeutic approach for conditions like autism and epilepsy.

The study, published in Nature, investigated experience-dependent plasticity – the ability of neurons to change their properties in response to experiences. Dysfunction in this process has been implicated in some of the cognitive and neurological symptoms associated with NDDs.

Identifying a key plasticity gene

The researchers screened genes involved in the plasticity of parvalbumin inhibitory neurons, a specific type of brain cell involved in regulating neuronal activity.

The researchers identified Meis2 as a candidate of particular interest. The gene was expressed at relatively low levels in parvalbumin inhibitory neurons but increased in response to experience, suggesting that it may play a role in regulating experience-dependent changes in these cells.

The team, led by co-first authors Dr Yu-Tzu Shih and Dr Jason Alipio, then investigated whether increasing Meis2 expression could restore impaired neuronal function.

“Cognitive impairment and seizures are hallmarks of neurodevelopmental disorders and represent a large, unmet clinical need,” said senior author Dr Amar Sahay 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.”

Gene therapy restores brain function in mice

Using gene therapy to increase Meis2 expression in parvalbumin inhibitory neurons, the researchers tested the approach in a widely used mouse model of NDDs.

The intervention rebalanced excitation and inhibition in the brain and restored experience-dependent plasticity. Mice receiving the treatment also showed improvements in spatial and social memory.

The researchers also saw a reduction in seizure frequency following Meis2 overexpression. Abnormalities in brain network activity associated with cognition were also corrected, indicating that targeting the gene could produce effects across several aspects of NDD-related dysfunction.

The findings provide proof-of-concept evidence that restoring neuronal plasticity could potentially address developmental deficits even after they have become established.

From mechanism to potential therapy

Despite the encouraging preclinical findings, translating the approach into a treatment for people with NDDs will require further research. 

“The development of new therapeutics for NDDs is dependent on understanding the mechanisms by which risk genes cause impairments,” said Dr 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.”