Fragile X Phenotypes Reversed in Mice by Targeting NMDA Receptors

Fragile X Phenotypes Reversed in Mice by Targeting NMDA Receptors

A new study suggests a potential molecular strategy for treating fragile X syndrome, an inherited neurodevelopmental disorder that causes autism spectrum disorder and intellectual disability. This work shows that enhancing the function of the GluN2b subunit of the N-methyl-D-aspartate (NMDA) receptor signaling pathway can correct key neural dysfunctions in a mouse model of fragile X syndrome.

The research, titled “Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes,” was published in Cell Reports.

Led by Mark Bear, PhD, at MIT’s Picower Institute for Learning and Memory, the study builds on previous work by this group exploring the role of NMDA receptors in regulating synaptic plasticity. The group studies synaptic plasticity and has a history of exploring the molecular basis of fragile X syndrome, and a related disorder, tuberous sclerosis (Tsc).

“We ended up here by accident at the end of the last century, following up on studies of the basic neurobiology of synaptic plasticity. One of our discoveries suggested the possibility that we could reverse aspects of fragile X syndrome, and we have stuck with it for 25 years,” Bear shared with GEN.

Fragile X is characterized by excessive protein synthesis, which leads to synaptic dysfunction and predisposition to seizures, while Tsc involves reduced protein synthesis. In fact, crossbreeding mouse models of both conditions results in healthy offspring, with the protein expression levels balancing each other.

NMDA receptors play a critical role in synaptic plasticity, where calcium ions flow through the receptor and contribute to long-term depression. More recent work from the group identified a signaling pathway for NMDA that was independent of ion flow.

The team hypothesized that two subunits of NMDA, GluN2A and GluN2B, have separate functions contributing to the two functional pathways, with GluN2A contributing to synaptic function via ion flow, while GluN2B modifies protein synthesis through the non-ionotropic mechanism.

To test these hypotheses, the team used the shrinkage and enlargement of dendritic spines as a physical marker for synaptic plasticity in response to modifications in NMDA function. Knockout experiments showed that loss of either GluN2A or GluN2B disrupted long-term depression, a consequence of ionotropic signaling. Knocking out GluN2B eliminated spine shrinkage, a hallmark of synaptic plasticity through non-ionotropic signaling.

Bear commented that by using this method, the team “discovered a novel approach to rebalance altered protein synthesis regulation in these diseases, one that had not been known before.”

The MIT researchers genetically engineered mice in which the carboxy-terminal domain (CTD) of GluN2B was swapped with that of GluN2A. They found that disrupting GluN2B’s CTD eliminated its ability to regulate spine size and increased bulk protein synthesis, mirroring what is seen in fragile X syndrome. Conversely, enhancing GluN2B signaling reduced protein synthesis to normal levels, similar to what is observed in Tsc models.

They then tested whether increasing GluN2B signaling could counteract fragile X-like phenotypes. Fragile X model mice were treated with Glyx-13, which selectively binds to GluN2B. Treatment normalized protein synthesis and reduced seizure susceptibility in fragile X model mice, suggesting that targeting GluN2B could represent a novel therapeutic approach for fragile X syndrome.

“These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X and related causes of intellectual disability and autism,” the authors wrote.

By putting together data collected over decades, the MIT researchers identified a deeper understanding of a signaling pathway with broad implications for neurological disorders. Bear pointed out to GEN that “fragile X and TSC are monogenic causes of autism spectrum disorder.” He continued, “We expect that insights gained by studying these diseases will be broadly applicable.”

“One of the things I find most satisfying about this study is that the pieces of the puzzle fit so nicely into what had come before,” said Bear.

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