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Nat. Commun., May 29 2026, | https://doi.org/10.1038/s41467-026-73881-9 Glycine-modulating Slc6a20a-ASO restores NMDA receptor function in SHANK2 and SHANK3-mutant mice and cortical organoids

Junyeop Daniel Roh^1,*, Mihyun Bae^1,*, Yusang Oh^2,*, Yeji Yang^2,3, Suho Lee¹, Woo-Chang Hwang^4,5, Esther Yang⁶, Hyeonji Kim⁷, Hyunjee Jang⁷, Hyung-Wook Choi⁷, Hyun Kim⁶, Jin Young Kim³, and Eunjoon Kim^1,2,#

¹Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 34141, Korea;
²Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea;
³Digital Omics Research Center, Korea Basic Science Institute, Ochang 28119, Korea;
⁴Department of Pre-medicine, Hanyang University College of Medicine, Seoul 04763, Korea;
⁵HY Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Korea;
⁶Department of Anatomy and Brain Korea 21 Graduate Program, Biomedical Science, College of Medicine, Korea University, Seoul, 02841, Korea;
⁷Bertis Inc., Gwacheon, Korea;

^*These authors contributed equally to the work;
^#Corresponding author

Abstract

Suppressed NMDA receptor (NMDAR) function contributes to multiple brain disorders, including schizophrenia, autism spectrum disorder (ASD), and NMDAR encephalitis. Previous attempts to restore NMDAR activity by increasing ambient glycine, a critical co-agonist, through GlyT1 inhibition have yielded mixed outcomes, partly due to GlyT1's extensive expression in essential brainstem regions. Slc6a20a, a glycine transporter widely expressed in cognition-relevant regions such as the cortex and hippocampus, offers a targeted alternative. Here we show that antisense oligonucleotide (ASO)-mediated Slc6a20a inhibition (Slc6a20a-ASO) normalizes ASD-related phenotypes in male Shank2- and Shank3-mutant mice, with model-dependent rescue profiles. Slc6a20a-ASO rescues NMDAR hypofunction and synaptic phospho-proteomic profiles in the prefrontal cortex. Furthermore, ASO targeting human SLC6A20 rescues suppressed NMDAR function in cortical organoids harboring SHANK2 or SHANK3 mutations. These findings underscore the potential and limitations of Slc6a20a/SLC6A20-ASO for treating disorders characterized by NMDAR hypofunction.

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