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Building on over two decades of research, neuroscientists at the Massachusetts Institute of Technology’s (MIT) Picower Institute for Learning and Memory have discovered a novel method to treat the pathology and symptoms of fragile X syndrome, the most common genetically caused autism spectrum disorder. Their findings, published in Cell Reports, indicate that enhancing a specific neurotransmitter signaling pathway can reduce the disorder’s hallmarks in mouse models.
A New Approach to Treatment
The study focuses on a specific molecular subunit of NMDA receptors, which play a crucial role in how neurons synthesize proteins to regulate synaptic connections. By increasing the receptor’s activity, researchers observed a suppression of excessive bulk protein synthesis in hippocampal neurons—an abnormality associated with fragile X syndrome. This molecular adjustment led to improvements in synaptic plasticity and neuronal function.
Connecting the Dots
Senior author Mark Bear, Picower Professor at MIT’s Department of Brain and Cognitive Sciences, emphasized how the study builds upon previous research. Lead author Dr. Stephanie Barnes, now a lecturer at the University of Glasgow, contributed significantly to uncovering the role of NMDA receptors in fragile X syndrome.
Past research from Bear’s lab had established that fragile X syndrome and tuberous sclerosis (Tsc), another autism-related disorder, exist on opposite ends of a spectrum of neuronal protein synthesis. While fragile X results in excessive protein synthesis, Tsc leads to insufficient synthesis. When researchers crossbred mice carrying mutations for both conditions, the resulting offspring displayed a balanced neurological state, suggesting that regulating protein synthesis could be key to treatment.
In 2020, Bear’s team identified a non-ionic mode of NMDA receptor signaling that affects protein synthesis and dendritic spine structures—critical components for neural connectivity. Their latest study builds on this discovery, pinpointing the NMDA receptor’s GluN2B subunit as a major player in protein synthesis regulation.
Targeting the GluN2B Subunit
To investigate the role of NMDA receptor subunits, researchers selectively knocked out GluN2A and GluN2B in hippocampal neurons. While both subunits were essential for synaptic function, only the GluN2B subunit influenced dendritic spine morphology and bulk protein synthesis.
Further experiments involving genetically engineered mice from the University of Edinburgh demonstrated that the carboxyterminal domain (CTD) of the GluN2B subunit is crucial for regulating protein synthesis. When researchers swapped the CTD with that of GluN2A, the ability to control bulk protein synthesis was lost. Conversely, augmenting GluN2B signaling restored protein synthesis balance, mimicking the effects seen in tuberous sclerosis.
Promising Therapeutic Potential
Encouraged by these findings, researchers tested an experimental drug, Glyx-13, which binds to the GluN2B subunit and enhances NMDA receptor signaling. Treatment with Glyx-13 normalized protein synthesis and reduced sound-induced seizures in fragile X model mice.
While the clinical potential of Glyx-13 remains uncertain, Bear noted that pharmaceutical research is underway to develop drugs targeting the GluN2B subunit, offering hope for future treatment options for fragile X syndrome and related disorders.
Future Directions
The researchers hypothesize that modulating GluN2B signaling may shift protein synthesis patterns, reducing excessive translation of short messenger RNAs and favoring a more balanced protein production process. These findings provide a compelling new avenue for therapeutic development.
Conclusion
This study marks a significant step toward understanding and potentially treating fragile X syndrome through targeted molecular interventions. While further research and clinical trials are needed, the discovery offers hope for individuals affected by this condition and underscores the importance of continued exploration in neurodevelopmental disorders.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. The findings discussed are based on animal models and have not yet been tested in human clinical trials. Individuals should consult healthcare professionals for medical concerns related to fragile X syndrome or other neurological disorders.
