Fragile X syndrome is the most common genetically-caused autism spectrum disorder. It causes a range of developmental issues, including intellectual disabilities and behavioral challenges.
Based on more than two decades of research, MIT neuroscientists at The Picower Institute for Learning and Memory have developed a new way to treat the pathology and symptoms of fragile X syndrome.
Their approach mainly targets a specific molecular subunit of “NMDA” receptors, which plays a vital role in how neurons synthesize proteins to regulate their connections, or “synapses,” with other neurons in brain circuits.
In mouse models with disorders, the team found that augmenting a novel type of neurotransmitter signaling reduced hallmarks of fragile X. In particular, it increased the receptor’s activity, causing neurons in the brain’s hippocampus region to increase molecular signaling that suppressed excessive bulk protein synthesis, leading to other key improvements.
At the lab of the study’s senior author, Mark Bear, Picower Professor in MIT’s Department of Brain and Cognitive Sciences, the team studies ‘synaptic plasticity’, which underlies the brain’s ability to adapt to experience and to form and process memories.
In 2011, researchers at Bear’s lab discovered that fragile X syndrome (FXS) and tuberous sclerosis (Tsc), both of which are autism-related disorders, affect protein production in brain cells in opposite ways.
In FXS, there’s an excess of protein, while in Tsc, there’s a deficiency. When scientists bred mice with FXS and Tsc together, their offspring were healthy because the two mutations canceled each other out.
Recently, Bear’s lab made a new discovery. They had already shown that calcium ions flowing through NMDA receptors can trigger “long-term depression” (LTD), a type of brain plasticity.
However, in 2020, they found that NMDA receptors can also change protein production in brain cells without ion flow, causing parts of the cells (dendritic spines) to shrink.
For researchers Bear and Barnes, this raised the possibility that understanding how NMDA receptors control protein production could lead to new treatments for fragile X syndrome and tuberous sclerosis.
This would add to their ongoing work on correcting protein levels in fragile X using another receptor called mGluR5.
In this new study, researchers used the effect on spine shrinkage to understand how NMDA receptors signal protein synthesis for synaptic plasticity in hippocampus neurons.
They hypothesized that the effects on synaptic function and spine structure might come from two components of NMDA receptors: subunits GluN2A and GluN2B.
They used genetic techniques to remove each subunit. When they did, they found that removing either “2A” or “2B” stopped LTD, but only removing “2B” affected spine size. Further experiments showed that 2A and 2B are needed for LTD, but spine shrinkage depends only on the 2B subunit.
The next step was determining how the 2B subunit signals spine shrinkage. Researchers suspected a part of the subunit called the “carboxyterminal domain” (CTD) was responsible. They used genetically modified mice from the University of Edinburgh, where the 2A and 2B CTDs could be swapped.
When the 2B subunit lacked its CTD, the spine shrinkage effect disappeared, confirming that the 2B subunit signals spine shrinkage via its CTD.
Replacing the CTD of the 2B subunit increased protein production, similar to what is seen in fragile X syndrome. On the other hand, enhancing the non-ionic signaling through the 2B subunit reduced protein production, similar to what happens in tuberous sclerosis.
Adult brain contains millions of ‘silent synapses,’ study
Researchers found that increasing signaling through the 2B subunit could help treat fragile X syndrome (FXS), similar to how a mutation causing tuberous sclerosis (Tsc) can help. When they swapped the 2B subunit CTD of NMDA receptors in fragile X mice, they corrected the excessive protein production, altered synaptic plasticity, and reduced electrical excitability.
They tested an experimental drug called Glyx-13, which binds to the 2B subunit to boost signaling. This drug normalized protein synthesis and reduced sound-induced seizures in fragile X mice.
The researchers believe the 2B subunit’s CTD signaling shifts protein production from short messenger RNAs to longer ones, helping to balance protein levels. While it’s unclear if Glyx-13 will become a clinical drug, other drugs targeting the 2B subunit are developing.
Journal Reference
- Stephanie A. Barnes, Aurore Thomazeau, Peter Finnie et al. Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes. Cell Reports. DOI: 10.1016/j.celrep.2025.115311
