New Autism Therapy Shows Surprising Benefits Even in Adult Mice

A groundbreaking study has made a significant breakthrough in the treatment of autism spectrum disorder (ASD) by restoring disrupted brain signaling and easing autism-related behaviors.

Researchers at the Institute for Basic Science (IBS) led by Director Eunjoon Kim have discovered a potential new way to treat ASD by targeting a specific brain receptor known as Slc6a20a/SLC6A20. This receptor plays a crucial role in communication between brain cells and is essential for learning, memory, and other cognitive processes.

Reduced NMDA receptor (NMDAR) activity has been linked to several neurological and psychiatric conditions, including ASD, schizophrenia, intellectual disability, and NMDAR encephalitis. For decades, scientists have been searching for ways to improve NMDAR function, but clinical studies have produced inconsistent results. In an attempt to find a more targeted approach, researchers have turned their attention to the glycine transporter Slc6a20a.

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. The researchers used antisense oligonucleotides (ASOs) to reduce Slc6a20a expression 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.

Using large-scale phospho-proteomic analyses, the researchers 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.

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.

Director Eunjoon Kim noted, ‘Unlike gene re-expression strategies, SLC6A20 inhibition works by modulating endogenous signaling pathways and may offer a more practical therapeutic route. 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.’

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 and offer a possible foundation for developing treatments for a broader group of neurodevelopmental and neuropsychiatric disorders involving NMDAR hypofunction.