New autism therapy shows surprising benefits even in adult mice

Researchers have uncovered a potential new way to treat autism spectrum disorder (ASD) by restoring the function of an important brain receptor. The study, led by Director Eunjoon Kim of the IBS Center for Synaptic Brain Dysfunctions, focused on a glycine transporter known as Slc6a20a/SLC6A20.

The team found that reducing the activity of this transporter could help restore NMDA receptor (NMDAR) function. These receptors play a major role in communication between brain cells and are essential for learning, memory, and other cognitive processes.

A More Targeted Way to Restore Brain Signaling

Reduced NMDAR activity has been linked to several neurological and psychiatric conditions, including autism spectrum disorder (ASD), schizophrenia, intellectual disability, and NMDAR encephalitis. Scientists have spent decades searching for ways to improve NMDAR function, but clinical studies have produced inconsistent results. Those setbacks have increased interest in treatments that can act more precisely.

For an NMDA receptor to become fully active, it needs both glutamate and glycine. Earlier treatment strategies tried to raise glycine levels by blocking GlyT1, another transporter that regulates glycine.

That approach created problems because GlyT1 is common in parts of the brainstem that help control breathing and movement. As a result, treatments targeting GlyT1 often provided limited benefits and caused unwanted side effects.

The researchers chose a different target. Slc6a20a is found mainly in brain regions involved in cognition, including the cortex and hippocampus. Its more restricted location could make it possible to improve NMDAR activity while reducing effects on other essential brain functions.

Treatment Improves Brain Function and Behavior

The team used antisense oligonucleotides (ASOs) to reduce Slc6a20a expression. They tested the treatment in mouse models with mutations in SHANK2 and SHANK3. These two major autism risk genes are also connected to Phelan-McDermid syndrome and other neurodevelopmental disorders.

Treatment with Slc6a20a ASO restored NMDAR activity in several mouse models related to autism. It also improved difficulties involving social interaction, social communication, and repetitive behaviors.

Notably, the benefits appeared in adult mice. This finding suggests that NMDAR dysfunction may still be treatable after major stages of brain development are complete.

The researchers then examined how the treatment produced these effects. Using large-scale phospho-proteomic analyses, they found that the therapy caused relatively little change in the total amounts of proteins.

Instead, the treatment corrected abnormal phosphorylation patterns in proteins that regulate synaptic signaling and NMDA receptors. This result suggests that the approach restores the way proteins function rather than simply increasing or decreasing how much of each protein is present.

Similar Results in Human Brain Organoids

To explore whether the strategy might eventually have relevance for people, the researchers tested it in human brain models.

Using CRISPR gene editing, they created human cortical organoids with SHANK2 or SHANK3 mutations. Like the mouse models, these organoids showed reduced NMDAR activity.

An ASO designed to target the human SLC6A20 gene restored NMDAR function to levels close to normal.

"Unlike gene re-expression strategies, SLC6A20 inhibition works by modulating endogenous signaling pathways and may offer a more practical therapeutic route," said Director Eunjoon Kim. "The fact that the effect was reproduced not only in mice but also in human cortical organoids suggests that this approach may represent a promising therapeutic strategy for neurodevelopmental disorders characterized by NMDA receptor hypofunction."

Effects Lasted for at Least Eight Weeks

The researchers also reported that one administration of the ASO remained effective for at least 8 weeks. No detectable adverse effects were found in the treated mice during that period.

Although the study centered on autism spectrum disorder, the approach could have wider applications. Reduced NMDAR activity is also associated with schizophrenia and certain forms of intellectual disability.

The results identify SLC6A20 as a promising target for restoring NMDAR function. They also offer a possible foundation for developing treatments for a broader group of neurodevelopmental and neuropsychiatric disorders involving NMDAR hypofunction.

Reporting from ScienceDaily contributed to this story.