Researchers have identified a promising new therapeutic strategy for autism spectrum disorder (ASD). A research team led by Director KIM Eunjoon of the IBS Center for Synaptic Brain Dysfunctions has now identified a promising new strategy for restoring NMDA receptor (NMDAR) function by targeting a glycine transporter called Slc6a20a/SLC6A20.

Impaired NMDAR function has long been implicated in a range of brain disorders, including autism spectrum disorder (ASD), schizophrenia, intellectual disability, and NMDAR encephalitis. Despite decades of research, attempts to restore NMDAR activity have produced mixed clinical results, highlighting the need for more precise therapeutic approaches.

The NMDA receptor requires not only glutamate but also glycine to become fully activated. Previous therapeutic approaches attempted to increase glycine levels by inhibiting GlyT1, another glycine transporter. However, because GlyT1 is widely expressed in brainstem regions involved in breathing and motor control, such treatments often produced limited benefits and undesirable side effects.

The researchers instead focused on Slc6a20a, a glycine transporter predominantly expressed in cognition-related brain regions such as the cortex and hippocampus.

Using antisense oligonucleotides (ASOs) to suppress Slc6a20a expression, the team investigated whether NMDAR function could be restored in mouse models carrying mutations in SHANK2 and SHANK3, two major autism-risk genes that are also associated with Phelan-McDermid syndrome and other neurodevelopmental disorders.

The results showed that Slc6a20a-ASO successfully restored NMDAR activity in multiple autism-related mouse models. The treatment also improved several behavioral abnormalities, including impairments in social interaction, social communication, and repetitive behaviors. Importantly, these therapeutic effects were observed in adult animals, suggesting that correction of NMDAR dysfunction may remain possible even after key stages of brain development have passed.

To understand the underlying mechanism, the researchers performed large-scale phospho-proteomic analyses. Surprisingly, the treatment had relatively little effect on overall protein abundance. Instead, it restored abnormal phosphorylation patterns in proteins involved in synaptic signaling and NMDA receptor regulation, suggesting that the therapy works by normalizing protein function rather than simply changing protein levels.

To evaluate its translational potential, the team extended the study to human brain models.

Using CRISPR gene editing, the researchers generated human cortical organoids carrying SHANK2 or SHANK3 mutations. These organoids exhibited reduced NMDAR activity similar to that observed in the mouse models. Treatment with an ASO targeting the human SLC6A20 gene restored NMDAR function to near-normal levels.

“Unlike gene re-expression strategies, SLC6A20 inhibition works by modulating endogenous signaling pathways and may offer a more practical therapeutic route,” said Director KIM Eunjoon. “The fact that the effect was reproduced not only in mice but also in human cortical organoids suggests that this approach may represent a promising therapeutic strategy for neurodevelopmental disorders characterized by NMDA receptor hypofunction.”

The researchers also found that a single administration of the ASO remained effective for at least 8 weeks without detectable adverse effects in the treated mice.

Beyond autism spectrum disorder, the findings may have broader implications for other neurological and psychiatric conditions associated with reduced NMDAR activity, including schizophrenia and certain forms of intellectual disability.

The findings establish SLC6A20 as a promising therapeutic target for restoring NMDAR function and provide a potential framework for treating a broader range of neurodevelopmental and neuropsychiatric disorders linked to NMDAR hypofunction.

Figure 1. Treatment of mutant autism mouse models and human cortical organoids using Slc6a20a/SLC6A20-ASO
ASO restored social interaction deficit, excessive self-grooming in mouse models and NMDA receptor hypofunction in mouse models and human cortical organoids.