Researchers at the Institute for Basic Science in South Korea identified the glycine transporter SLC6A20 as a target for restoring NMDA receptor function, which is reduced in several neurodevelopmental conditions including autism spectrum disorder. Unlike the more widely distributed transporter GlyT1, SLC6A20 is concentrated in cortical and hippocampal regions involved in cognition, offering a potentially more selective intervention point.
The team used antisense oligonucleotides to reduce SLC6A20 expression in mouse models carrying mutations in SHANK2 or SHANK3, two high-confidence autism risk genes also linked to Phelan-McDermid syndrome. Treatment restored NMDA receptor currents in brain slices and improved performance on assays of social interaction, social communication, and repetitive behavior.
Notably, the behavioral improvements were observed in adult mice, suggesting that NMDA receptor hypofunction remains reversible after early developmental windows have closed. Phospho-proteomic analysis showed the treatment corrected abnormal phosphorylation patterns in synaptic signaling proteins rather than broadly altering protein abundance.
To test translational relevance, the researchers generated human cortical organoids with CRISPR-engineered SHANK2 or SHANK3 mutations. These organoids exhibited reduced NMDA receptor activity, which was restored to near-normal levels by an ASO targeting the human SLC6A20 gene.
A single ASO administration remained effective for at least eight weeks in mice, with no detectable adverse effects during that period. The authors note that reduced NMDA receptor activity is also implicated in schizophrenia and certain intellectual disabilities, indicating the strategy may apply to a broader set of neuropsychiatric conditions.
The study was published in Nature Communications on August 7, 2026, led by Director Eunjoon Kim of the IBS Center for Synaptic Brain Dysfunctions. The findings are based on preclinical models; clinical safety and efficacy in humans have not yet been established.
New autism therapy shows surprising benefits even in adult mice
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