Director KIM Eunjoon's team at South Korea's IBS Center for Synaptic Brain Dysfunctions has identified a novel therapy that restores a crucial brain receptor implicated in autism spectrum disorder—and the breakthrough works even in adult brains, long after critical developmental windows have closed.
The finding addresses a decades-old puzzle in neuroscience. NMDA receptors, which require both glutamate and glycine to activate fully, have been linked to autism, schizophrenia, intellectual disability, and other neurological conditions. Previous attempts to boost NMDA receptor function by inhibiting a glycine transporter called GlyT1 had mixed results and triggered side effects because GlyT1 is spread throughout the brainstem, which controls breathing and movement.
KIM's team took a different approach. They targeted SLC6A20, a glycine transporter found primarily in brain regions governing cognition—the cortex and hippocampus. Using antisense oligonucleotides (ASOs) to suppress SLC6A20 expression, they tested the therapy in mouse models carrying mutations in SHANK2 and SHANK3, two genes strongly linked to autism and Phelan-McDermid syndrome.
The results were striking. In adult mice, SLC6A20-targeting ASOs restored NMDAR activity and reversed several behavioral hallmarks of autism: impaired social interaction, social communication difficulties, and repetitive self-grooming behaviors. Even more remarkably, these improvements persisted in fully developed animals, suggesting that correcting NMDAR dysfunction may be possible years after development—opening doors for treating people diagnosed as children or adults.
To understand how the therapy worked, the researchers conducted large-scale phospho-proteomic analyses. They discovered something unexpected: the ASO didn't simply increase protein levels. Instead, it normalized abnormal phosphorylation patterns in proteins controlling synaptic signaling and NMDA receptor regulation, essentially restoring the brain's ability to use its existing molecular machinery more effectively.
The team then tested the approach in human cortical organoids—tiny lab-grown brain structures—engineered using CRISPR gene editing to carry SHANK2 or SHANK3 mutations. These organoids showed the same NMDAR dysfunction as the mice. When treated with an ASO targeting the human SLC6A20 gene, NMDAR function rebounded to near-normal levels. "Unlike gene re-expression strategies, SLC6A20 inhibition works by modulating endogenous signaling pathways and may offer a more practical therapeutic route," KIM explained.
The durability is another advantage. A single ASO dose remained effective for at least eight weeks in mice without detectable adverse effects—suggesting the therapy could eventually become practical for patients, potentially requiring only periodic treatments rather than constant medication.
Published in Nature Communications, the findings establish SLC6A20 as a promising therapeutic target with implications extending well beyond autism. Reduced NMDAR activity underlies schizophrenia, certain intellectual disabilities, and NMDAR encephalitis, meaning this approach could eventually help people across multiple conditions and age groups. For families navigating autism diagnosis, the message is clear: dysfunction in the adolescent or adult brain may be reversible after all.