Researchers have identified a potential new treatment strategy for autism spectrum disorder (ASD) by restoring the function of a key brain receptor. The study, led by Eunjoon Kim, director of the IBS Center for Synaptic Brain Dysfunctions, examined a glycine transporter called Slc6a20a in mice and human brain organoids.
The researchers found that reducing the activity of this transporter may restore NMDA receptor (NMDAR) function. NMDARs are essential for communication between brain cells and play important roles in learning, memory, social behavior, and other cognitive processes.
A More Targeted Approach to Restoring NMDAR Function
Reduced NMDAR activity, also known as NMDAR hypofunction, has been associated with several neurological and psychiatric conditions, including autism spectrum disorder, schizophrenia, intellectual disability, and NMDAR encephalitis. Although scientists have spent decades developing treatments to enhance NMDAR function, clinical results have often been inconsistent. This has increased interest in more targeted therapies.
For an NMDA receptor to become fully active, it requires both glutamate and glycine. Previous treatment approaches attempted to increase glycine levels by blocking GlyT1, a transporter that regulates glycine in the brain.
However, GlyT1 is widely distributed in brainstem regions involved in breathing and movement. As a result, GlyT1-targeting treatments have produced limited benefits while also increasing the risk of unwanted side effects.
The researchers focused instead on Slc6a20a, a transporter found primarily in brain regions involved in cognition, including the cortex and hippocampus. Its more restricted distribution could allow scientists to enhance NMDAR activity while minimizing effects on other essential brain functions.
Experimental Treatment Improves Brain Function and Behavior
The team used antisense oligonucleotides (ASOs) to reduce Slc6a20a expression. The treatment was tested in mouse models carrying mutations in SHANK2 and SHANK3, two important autism-related genes that are also associated with Phelan-McDermid syndrome and other neurodevelopmental disorders.
In several mouse models of autism, treatment with Slc6a20a-targeting ASOs restored NMDAR activity. The therapy also improved behavioral difficulties related to social interaction, social communication, and repetitive behaviors.
Importantly, the improvements were observed in adult mice. This finding suggests that NMDAR dysfunction could remain responsive to treatment even after major stages of brain development have ended.
The researchers then investigated how the treatment produced its effects. Using large-scale phosphoproteomic analysis, they found that the therapy caused relatively few changes in the overall amounts of proteins in the brain.
Instead, the ASO treatment corrected abnormal phosphorylation patterns in proteins involved in synaptic signaling and NMDA receptor regulation. This suggests that the therapy may restore how signaling proteins function rather than simply increasing or decreasing their total levels.
Similar Results Found in Human Brain Organoids
To determine whether the findings could have potential relevance to human disorders, the researchers tested the treatment in human brain models.
Using CRISPR gene editing, they created human cortical organoids with SHANK2 or SHANK3 mutations. Like the mouse models, these organoids showed reduced NMDAR activity.
An antisense oligonucleotide designed to target the human SLC6A20 gene restored NMDAR function to levels close to those seen in healthy organoids.
“Unlike gene re-expression strategies, SLC6A20 inhibition works by modulating endogenous signaling pathways and may offer a more practical therapeutic route,” said Director Eunjoon Kim. “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.”
Effects Continued for at Least Eight Weeks
The researchers reported that a single administration of the ASO remained effective for at least eight weeks. During that period, the treated mice showed no detectable adverse effects.
Although the study focused on autism spectrum disorder, the treatment strategy may have broader applications. NMDAR hypofunction has also been linked to schizophrenia, certain forms of intellectual disability, and other neurodevelopmental and neuropsychiatric conditions.
These findings identify SLC6A20 as a potential therapeutic target for restoring NMDA receptor function. The research may help guide the development of future treatments for autism and other disorders associated with impaired NMDAR signaling. However, additional studies are needed to determine the safety, effectiveness, and potential clinical use of this approach in humans.
Source: www.sciencedaily.com