Retinoid X Receptor Gamma as a Potential Therapeutic Target for Fragile X Syndrome

The proposed research project addresses the 'Fragile X Syndrome' topic area by seeking to understand the molecular mechanisms that underlie the disease and test a new therapeutic approach for its treatment. The proposed research project also addresses the gap and priority research area of 'epilepsy' by seeking to develop a novel pharmacological intervention for reducing seizures associated with fragile X syndrome and other forms of epilepsy.

The rationale for our proposal is based on our recent unpublished discovery that loss of a particular hormone receptor protein, the RXR gamma subunit, reduces the activity of a biochemical process, metabotropic glutamate receptor signaling, that contributes to symptoms associated with fragile X syndrome. This relationship between RXR gamma and metabotropic glutamate receptor signaling was previously unknown. Since inhibiting metabotropic glutamate receptor signaling has been found to reduce fragile X-related symptoms in humans and animal models, our discovery provides the opportunity for novel insights into the molecular mechanisms underlying this disorder and suggests that inhibiting RXR gamma may constitute a novel therapeutic strategy for the treatment or prevention of fragile X syndrome. Since increased metabotropic glutamate receptor signaling is also thought to contribute to seizures in fragile X patients, this discovery also suggests that inhibiting RXR gamma may constitute a novel therapeutic strategy for reducing seizures associated with fragile X syndrome and perhaps other forms of epilepsy.

The proposed research project will test two main hypotheses:

(1) That genetically reducing the level of the RXR gamma protein will prevent fragile X syndrome-related symptoms in an animal model of the disease.

To test this hypothesis, we will compare the structure of neurons and their electrical properties as well as the behavioral performance of mice that carry the fragile X syndrome mutation to animals that carry both the fragile X syndrome mutation and a mutation that eliminates the RXR gamma protein. If our hypothesis is true, then we expect that animals carrying both of these mutations will be more similar to their control siblings in these measures than to animals that carry the fragile X syndrome mutation alone.

(2) That drugs that inhibit the RXR gamma protein will prevent fragile X syndrome-related seizures and their underlying physiological changes in an animal model of fragile X syndrome.

To test this hypothesis, we will test currently available drugs that inhibit the RXR gamma protein for their ability to reduce fragile X syndrome-related seizures in mice that carry the fragile X mutation. We will also examine the effect of these drugs on the electrical properties of neurons that are thought to contribute seizure susceptibility.

If these hypotheses are correct, then this project will identify the RXR gamma protein as a new potential therapeutic target for the treatment or prevention of fragile X syndrome and/or epilepsy. The proposed project will also add to our understanding how of disruptions of the molecular processes that regulate the development and function of the nervous system produce the symptoms that characterize fragile X syndrome. Since the symptoms that characterize fragile X syndrome and the molecular processes that cause them share considerable overlap with other autism spectrum disorders, the mechanistic and therapeutic insights gained from the proposed project may also be applicable to understanding and treating other forms of autism that together are thought to affect 1 in 42 boys and 1 in 189 girls in the United States.