SLC6A20-Targeting ASO Restores NMDA Receptor Function in Autism Models, Offering New Therapeutic Strategy

A research team led by Director KIM Eunjoon at the IBS Center for Synaptic Brain Dysfunctions has identified a promising new therapeutic strategy for autism spectrum disorder (搜索)搜索该疾病 (ASD) by targeting a glycine transporter called Slc6a20a (SLC6A20 (搜索)搜索该靶点 in humans) to restore NMDA receptor (搜索)搜索该靶点 (NMDAR) function. The findings, published in Nature Communications, demonstrate that antisense oligonucleotide-mediated inhibition of this transporter can normalize NMDAR activity and reverse behavioral deficits in multiple preclinical models, including human cortical organoids.

Impaired NMDAR function has long been implicated in a range of brain disorders, including ASD, schizophrenia (搜索)搜索该疾病, 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.

A More Precise Target for Glycine Modulation

The NMDA receptor (搜索)搜索该靶点 requires both glutamate and glycine to become fully activated. Previous therapeutic strategies 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 IBS team instead focused on Slc6a20a, a glycine transporter predominantly expressed in cognition-related brain regions such as the cortex and hippocampus, while remaining sparse in brainstem motor centers. This localization profile offered the possibility of enhancing NMDAR function without triggering the respiratory and motor toxicity that plagued earlier GlyT1-targeted approaches.

Behavioral Rescue in Adult Mouse Models

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

The 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. Notably, 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.

Phospho-Proteomic Mechanism Revealed

To understand the underlying mechanism, the researchers performed large-scale phospho-proteomic analyses. 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 (搜索)搜索该靶点 regulation, indicating that the therapy works by normalizing protein function rather than simply changing protein levels.

Human Cortical Organoid Validation

To evaluate 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 (搜索)搜索该靶点 gene restored NMDAR function to near-normal levels.

"Unlike gene re-expression strategies, SLC6A20 (搜索)搜索该靶点 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 (搜索)搜索该靶点 hypofunction."

Durability and Broader Implications

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 ASD, the findings may have broader implications for other neurological and psychiatric conditions associated with reduced NMDAR activity, including schizophrenia (搜索)搜索该疾病 and certain forms of intellectual disability.

The study establishes SLC6A20 (搜索)搜索该靶点 as a promising therapeutic target for restoring NMDAR function and provides a potential framework for treating a broader range of neurodevelopmental and neuropsychiatric disorders linked to NMDAR hypofunction.