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<p>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 <i>GlyT1’s</i> 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 <i>Slc6a20a</i> inhibition (<i>Slc6a20a</i>-ASO) normalizes ASD-related phenotypes in male <i>Shank2</i>- and <i>Shank3</i>-mutant mice, with model-dependent rescue profiles. <i>Slc6a20a</i>-ASO rescues NMDAR hypofunction and synaptic phospho-proteomic profiles in the prefrontal cortex. Furthermore, ASO targeting human <i>SLC6A20</i> rescues suppressed NMDAR function in cortical organoids harboring <i>SHANK2</i> or <i>SHANK3</i> mutations. These findings underscore the potential and limitations of <i>Slc6a20a</i>/<i>SLC6A20</i>-ASO for treating disorders characterized by NMDAR hypofunction.</p>

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Glycine-modulating Slc6a20a-ASO restores NMDA receptor function in SHANK2 and SHANK3-mutant mice and cortical organoids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Junyeop Daniel Roh,
  • Mihyun Bae,
  • Yusang Oh,
  • Yeji Yang,
  • Suho Lee,
  • Woo-Chang Hwang,
  • Esther Yang,
  • Hyeonji Kim,
  • Hyunjee Jang,
  • Hyung-Wook Choi,
  • Hyun Kim,
  • Jin Young Kim,
  • Eunjoon Kim

摘要

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.