New approaches demonstrate the potential for treatment of vulnerable X syndrome

Based on more than 20 years of research, a study by MIT neuroscientists at Picower Institute for Learning and Memory treats the pathology and symptoms of vulnerable X syndrome, the most common genetically attributable autism spectrum disorder. We are reporting new ways to do this. The team showed that enhancing novel type of neurotransmitter signaling reduces the fragile X features in mouse models of disorders.

A new approach described in the cell report targets specific molecular subunits of the “NMDA” receptor, allowing neurons to synthesize proteins and connect or “synapse” with other neurons in the brain circuit. Discover that it plays an important role in how it is regulated. Scientists say that increasing receptor activity in vulnerable X-model mice causes neurons in the hippocampal region of the brain to suppress excess bulk protein synthesis and increase molecular signaling that leads to other important improvements. was shown.

Set the table

One of the things I find most satisfying about this study is that the puzzle pieces fit very well with what came before. ”

Mark Bear, senior study author, Professor Picower of Mitt’s Brain and Cognitive Sciences

Former postdoc Stephanie Burns, who is currently a lecturer at the University of Glasgow, is the lead author of the study.

Bear’s labs are studying how neurons can continuously edit circuit connections. This is a process called “synaptic plasticity,” which scientists believe is underlying the brain’s ability to adapt to experience, form and process memories. These studies have led to two findings that set a newly published table of advancements. In 2011, Bear’s Lab showed that fragile X and another autistic disorder, tuberous sclerosis (TSC), represent both ends of a continuum of protein synthesis of a type of neuron. It was too much for the vulnerable X. It was too little at TSC. When lab members crossed vulnerable X and TSC mice, in fact, the offspring became healthy as mutations in each disorder were essentially cancelled from each other.

More recently, Bear’s Lab has shown a different dichotomy. From their inventive research in the 1990s, we have long understood that the flow of calcium ions through NMDA receptors can trigger a form of synaptic plasticity called “long-term depression” (LTD). However, in 2020, they have a different effect by receptor 1, which requires neuronal ion flow alteration protein synthesis and does not cause physical reduction of the synapses that house the dendritic “spinal” structure. I discovered a signaling mode.

For Bear and Barnes, these studies can identify how NMDA receptors affect protein synthesis, and treat vulnerable X (and possibly tuberous sclerosis) pathology and symptoms. It raised the prospects that new mechanisms that can be operated can be identified. This is an important advancement to complement the ongoing working labs that Bear’s lab is making to correct vulnerable X protein synthesis levels through another receptor called MGLUR5.

Receptor Anatomy

In a new study, the team Bear and Burns decided to use the nonionic effect on spinal contraction as a readout to analyze NMDARS signal protein synthesis of synaptic plasticity in hippocampal neurons. They hypothesized that dichotomization of the ionic effects on synaptic function and nonionic effects on spinal structure could be derived from the presence of two different components of the NMDAR receptor. “Subunits” called Glun2a and Glun2b. To test it, they used genetic engineering to knock out each subunit. When they did so, they found that knocking out “2A” or “2B” could eliminate LTD, but only knocking out the spine size affected by 2B. Further experiments revealed that Ltd requires 2A and 2B, but its spinal contraction depends solely on the 2B subunit.

The next task was to resolve how the 2B subunit signaled spinal contraction. The promising possibility was part of a subunit called the “carboxy-terminal domain” or CTD. So, in a new experiment, Bear and Burns utilized mice that had been genetically modified by researchers at the University of Edinburgh to allow CTDs to be exchanged for each other. The results were that when the 2B subunit lacked appropriate CTD, the effects on spinal structure faded. Results confirmed that the 2B subunit signaled spinal contraction via the CTD.

Another result of replacing the CTD of the 2B subunit was an increase in bulk protein synthesis, similar to the findings of vulnerable X. Conversely, we enhanced nonionic signaling through inhibited bulk protein synthesis of the 2B subunit, which reminded us of TSCs.

Treatment for fragile x

Together, the findings show that enhancing signals through the 2B subunit may introduce vulnerable X rescue aspects, such as introducing mutations that cause TSCs. Ta.

In fact, when scientists exchanged for 2B subunit CTDs of NMDA receptors in vulnerable X-model mice, they altered not only excessive bulk protein synthesis, but also synaptic plasticity, and the electroexcitatory nature of disease. We also found an increase. To see if treatments targeting NMDA receptors could be effective in the vulnerable X, we tried an experimental drug called Glyx-13. This drug binds to the 2B subunit of the NMDA receptor to enhance signaling. Researchers found that this treatment can normalize protein synthesis and reduce healthy seizures in vulnerable X mice.

Based on another previous study in the lab, the team said that the beneficial effect of CTD signaling of the 2B subunit on vulnerable X mice will displace the balance of protein synthesis from highly efficient translation of short messenger RNAs. I have made the hypothesis that this is. (This leads to excessive bulk protein synthesis towards lower efficient translation of longer messenger RNAs).

Bear said he doesn’t know what the outlook for Glyx-13 as a clinical drug is, but noted that there are several drugs in clinical development that specifically targets the 2B subunit of the NMDA receptor. did.

In addition to Bear and Burns, other authors of this study are Auror Thomasö, Peter Finney, Max Heinreich, Arnold Heinen, Nobor Komiyama, Seth Grant, Frank Mennity and Emily Osterweil.

The Fraxa Foundation, Picower Institute for Learning and Memory, The Freedom Together Foundation, and the National Institutes of Health funded the research.