Scientists have created a new therapeutic approach for testing fragile X syndrome, which is the most common genetic cause of autism spectrum disorder (ASD). This method aims to alter a type of neural signaling involving neurotransmitter, and NMDA receptors. In a mouse model of fragile X, the treatment effectively reduced symptoms of ASD. The work has been published in Cell Reports.
NMDA receptors are known to be related to the production of proteins that regulate links between neurons, or synapses. Synpatic plasticity is a term that refers to the continuous alteration of the links or circuits between neurons, a process that is thought to be related to learning and memory. Researchers have long known that ion movement in NMDA receptors can lead to changes in synaptic efficacy known as long-term depression (LTD).
But more recently, scientists involved in this study determined that another type of NMDA receptor signaling that is unrelated to ions, can influence neuronal protein production. This can cause part of the neuronal cell to shrink, a process known as spinal shrinkage.
In a mouse fragile X model, there is an abnormal overproduction of some proteins in certain neurons.
In this study, the researchers wanted to know more about how NMDA receptors are related to the production of proteins in hippocampal neurons. They removed two different portions of the NMDA receptor in a mouse model: either GluN2A and GluN2B. This work showed that spinal shinkage in neurons is dependent on the 2B subunit, while both are necessary for LTD.
Additional work revealed that a portion of 2B called the carboxyterminal domain (CTD) is related to spinal shrinkage. When the CTD portion of 2B was altered, it also caused bulk protein synthesis to increase, which is similar to what is seen in fragile X. The researchers suspected that some symptoms of fragile X might be treatable by altering the 2B subunit to change signaling.
In a mouse model of fragile X, the researchers modified the CTD portion of the 2B subunit of NMDA receptors. This was shown to rescue excessive bulk protein production, synaptic plasticity, and abnormally increased electrical excitability that are known hallmarks of fragile X.
When the investigators used a drug called Glyx-13 that binds to NMDA receptors' 2B subunit, protein synthesis was reduced to normal levels, and the fragile X model mice had fewer sound-induced seizures.
The researchers don't know whether Glyx-13 could be useful as a drug for fragile X patients, but there are other drugs that are currently in development that aim specifically for the NMDA receptor 2B subunit, and may lead to a treatment for fragile X.
Sources: Picower Institute at MIT, Cell Reports