SLC6A20 ASO restores NMDA function in adult autism mice
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- Eunjoon Kim and the IBS Center for Synaptic Brain Dysfunctions targeted the glycine transporter Slc6a20a/SLC6A20, which is concentrated in cognition-related brain regions like the cortex and hippocampus, avoiding the brainstem exposure that derailed earlier GlyT1-targeting attempts.
- Antisense oligonucleotides reducing Slc6a20a expression restored NMDA receptor activity and improved social interaction, communication, and repetitive behaviors in mice carrying mutations in the autism risk genes SHANK2 and SHANK3, which are also linked to Phelan-McDermid syndrome.
- Adult mice showed the same behavioral and signaling improvements, with phospho-proteomic analyses showing the therapy corrected abnormal phosphorylation patterns in synaptic-signaling proteins rather than altering overall protein levels.
- CRISPR-edited human cortical organoids carrying SHANK2 or SHANK3 mutations showed reduced NMDAR activity that was restored to near-normal levels by an ASO designed against the human SLC6A20 gene.
- A single ASO dose remained effective for at least 8 weeks with no detectable adverse effects in treated mice, per the study published in Nature Communications.
- Kim said SLC6A20 inhibition modulates endogenous signaling pathways rather than re-expressing genes, calling the cross-species replication a promising foundation for treating neurodevelopmental and psychiatric disorders involving NMDAR hypofunction, including schizophrenia and certain intellectual disabilities.
Why it matters: Reduced NMDAR activity underlies autism, schizophrenia, and some intellectual disabilities, but decades of glycine-boosting drug attempts have failed due to side effects from hitting GlyT1 in the brainstem. By targeting the more regionally restricted SLC6A20, Kim's team offers a workaround that worked in adult mice and human organoids with a single dose lasting at least 8 weeks — evidence that the adult brain may still respond to NMDAR-restoring interventions once thought to require early development.
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