Scientists at the IBS Center for Synaptic Brain Dysfunctions have identified a new therapeutic target for treating autism spectrum disorder and related conditions. The research centered on Slc6a20a, a glycine transporter, and its role in regulating NMDA receptors, which are crucial for brain cell communication, learning, and memory. The team determined that reducing Slc6a20a activity could restore NMDAR function, which is known to be compromised in autism, schizophrenia, intellectual disability, and other neurological conditions.
Previous attempts to enhance NMDAR activity by blocking a related transporter called GlyT1 have yielded inconsistent clinical results and generated unwanted side effects, since GlyT1 is widely distributed in brain regions controlling basic functions like breathing and movement. The new approach targets Slc6a20a instead, which is concentrated primarily in cognitive centers including the cortex and hippocampus, potentially allowing for more selective therapeutic action with fewer complications.
In experiments using mouse models carrying mutations in autism-linked genes SHANK2 and SHANK3, researchers applied antisense oligonucleotides (ASOs) to suppress Slc6a20a expression. The treatment restored NMDAR activity and improved social interaction, social communication, and repetitive behaviors. Remarkably, these improvements occurred in adult mice, suggesting that NMDAR dysfunction may remain treatable after critical developmental periods conclude.
The research team extended their findings to human brain tissue models using CRISPR-edited cortical organoids with the same SHANK mutations. Treatment with human-targeted ASOs similarly restored NMDAR function to near-normal levels. A single ASO administration maintained effectiveness for at least eight weeks without detectable adverse effects in treated mice.
Because reduced NMDAR activity is implicated in multiple neurological and psychiatric conditions beyond autism, researchers suggest this therapeutic strategy could have broader applications. The results indicate SLC6A20 represents a viable target for developing treatments addressing NMDAR hypofunction across several neurodevelopmental and neuropsychiatric disorders.
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