Glycine transporter SLC6A20 target restores NMDAR function in autism spectrum disorder models
Researchers have identified a potential therapeutic strategy for autism spectrum disorder (ASD) by targeting the Slc6a20a glycine transporter to restore NMDA receptor (NMDAR) function. Led by Director Kim Eunjoon of the IBS Center for Synaptic Brain Dysfunctions, the study indicates that suppressing this specific transporter may normalize brain signaling pathways crucial for learning, memory, and social behavior.
Unlike previous attempts to boost brain activity by inhibiting the GlyT1 transporter—which is found throughout the brain and can cause respiratory side effects—the Slc6a20a transporter is primarily located in cognition-related regions like the cortex and hippocampus.
Restoring brain signaling
Impaired NMDAR function is linked to various neurological conditions, including schizophrenia, intellectual disabilities, and NMDAR encephalitis. According to the research team, NMDARs require both glutamate and glycine to function, but previous efforts to increase glycine levels often failed due to unwanted side effects in motor and respiratory control centers.
By using antisense oligonucleotides (ASOs) to suppress Slc6a20a, the researchers successfully restored NMDAR activity in mouse models carrying SHANK2 and SHANK3 gene mutations. These mutations are strongly associated with ASD and Phelan-McDermid syndrome. The treatment was effective even in adult mice, suggesting that correcting these signaling pathways may remain possible after critical developmental windows have closed.
Samantha Carter notes that the significance of this research lies in its focus on modulating endogenous signaling rather than attempting to re-express genes. By correcting abnormal protein phosphorylation patterns without altering total protein levels, this approach could offer a more precise and potentially safer therapeutic path for disorders characterized by NMDAR hypofunction.
From mice to human organoids
To determine if these findings could translate to human biology, the team utilized CRISPR gene-editing to create human cortical organoids with SHANK2 or SHANK3 mutations. These organoids exhibited the same reduced NMDAR activity observed in the mouse models. Treatment with an ASO targeting the human SLC6A20 gene restored receptor function to near-normal levels.
The researchers reported that a single administration of the ASO remained effective for at least eight weeks in mice with no detectable adverse effects. Director Kim Eunjoon stated that because the effect was reproduced across both mouse models and human organoids, this strategy may provide a framework for future treatments regarding neurodevelopmental and neuropsychiatric disorders.
Future clinical considerations
While the study provides a new model for targeting NMDAR hypofunction, the translation to clinical practice remains a future objective. If further research confirms these results, this method could potentially serve as a targeted intervention for conditions where reduced NMDAR activity is a primary driver of symptoms. Scientists expect that this mechanism-based approach will be tested further to verify long-term safety and efficacy in more complex biological systems.
Frequently Asked Questions
How does this treatment differ from previous attempts to restore NMDAR function?
Previous efforts focused on inhibiting the GlyT1 transporter, which is widespread in the brain and involved in motor and respiratory control. The new strategy targets Slc6a20a, which is concentrated in cognition-related regions like the cortex and hippocampus.
Did the treatment change the protein levels in the brain?
No. The study found that the treatment did not alter overall protein abundance but instead corrected abnormal phosphorylation patterns in proteins involved in synaptic signaling.
Is this treatment effective in adult subjects?
The study observed improvements in adult mouse models, which suggests that correcting NMDAR dysfunction may still be possible after the brain’s critical development periods have ended.
What other neurological conditions might benefit from this targeted approach to brain signaling?