Fragile X syndrome (FXS) is the most common genetically-caused autism spectrum disorder. The condition causes a number of developmental problems, including learning disabilities, cognitive impairment, social challenges, and behavioral difficulties. A recent study by MIT neuroscientists at The Picower Institute for Learning and Memory may offer a new treatment approach, building on more than two decades of research.
Years of Research Culminate in Fragile X Syndrome Breakthrough
The MIT study, published in Cell Reports, hones in on a specific molecular subunit of N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are glutamate receptors, serving as the human brain’s primary excitatory neurotransmitters. The researchers found that the molecular subunit plays a key role in how neurons synthesize proteins to regulate their synapses, or connections with other neurons, in brain circuits. By increasing the receptor’s activity in the FXS mouse model Fmr1-KO, the team caused hippocampus neurons to increase their molecular signaling, thereby suppressing excessive bulk protein synthesis characteristic of FXS, along with several other hallmarks of the disease. The finding wasn’t an isolated breakthrough; it was the result of years of deep research into FXS pathology, driven by the lab of study senior author Mark Bear, Picower Professor in MIT’s Department of Brain and Cognitive Sciences.
Pinpointing NMDA Receptors in Fragile X Pathology
In 2011, Bear’s lab explored similarities between fragile X syndrome and another autism disorder: tuberous sclerosis complex (TSC). The team found that the two disorders represented two ends of a continuum in terms of protein synthesis. In fragile X, protein synthesis was overactive, creating the excessive bulk protein synthesis observed in FXS. In TSC, protein synthesis was not active enough. Interestingly, when the team crossbred Fmr1-KO and TSC mice, their offspring emerged healthy. In other words, each disorder’s mutations canceled the other’s out.
Then, in 2020, Bear’s lab studied the flow of calcium ions through an NMDA receptor, a process known to trigger a form of synaptic plasticity. They found that another, non-ionotropic mode of signaling by the receptor altered protein synthesis, resulting in a notable shrinking of the dendritic spine structures, which receive signals from synapses.
The two studies raised an interesting question: Could Bear’s lab pinpoint how NMDA receptors affect protein synthesis? Moreover, could they use that information to create a therapeutic mechanism to address fragile X pathology and symptoms?
Moderating Synaptic Activity
Building on previous research, the MIT team concentrated on the non-ionotropic effect on synaptic spine shrinkage. The researchers used this as a readout, allowing them to dissect how NMDA receptors signal protein synthesis for synaptic plasticity in hippocampus neurons. They hypothesized that the ionotropic effects and non-ionotropic effects might derive from the presence of two distinct components of NMDA receptors: subunits called GluN2A and GluN2B.
To test the hypothesis, the researchers used genetic manipulations to knock out each of the subunits. Knocking out either GluN2A or GluN2B eliminated the troublesome form of synaptic plasticity — but only GluN2B affected synaptic spine size. How did GluN2B signal spine shrinkage?
The team focused on a subunit called the carboxyterminal domain, or CTD. They found that, when the GluN2B subunit lacked its proper CTD, the effect on spine structure disappeared. In other words, CTD was found to be the driving force behind synaptic spine shrinkage. This indicates that augmenting signaling through the GluN2B subunit could help treat certain aspects of fragile X, including excessive bulk protein synthesis, altered synaptic plasticity, and increased electrical excitability, all of which are hallmarks of the disease.
Perhaps the most important piece of the puzzle was determining whether a treatment targeting NMDA receptors could be effective in treating fragile X. To find out, the team tested an experimental drug called Glyx-13, which binds to the GluN2B subunit. It was ultimately found to normalize protein synthesis in the fragile X mice. It also reduced sound-induced seizures, another symptom of the disease.
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While the findings have not been tested on humans, the research suggests that non-ionotropic NMDA receptor signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X. Does Glyx-13 have potential as a clinical drug? The research isn’t clear — but GluN2B could very well be a druggable target.
To study autism spectrum disorders, Scantox Neuro offers preclinical research in the Fmr1-KO mouse model of fragile X syndrome as well as in BTBR mice. Mice can be treated with your compound against ASD symptoms and evaluated in vivo for disease-relevant behavioral alterations. Furthermore, tissues of these mouse models can be analyzed biochemically and histologically for disease pathologies and biomarkers. Tissues of Fmr1-Ko and BTBR mice can be provided through Scantox Neuro’s Biobank.
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