Fragile X syndrome (FXS) is a genetic disorder that causes the most common form of inherited intellectual disability and the leading known cause of autism spectrum disorders (ASD). FXS is caused by a loss of the fragile X mental retardation protein (FMRP). This loss is a result of a change in the fragile X mental retardation 1 (Fmr1) gene. Normal brain development requires FMRP because it is responsible for proper transport of proteins within brain cells that help with proper cell function. In addition to the intellectual disability, FXS patients suffer from sleeping disorders, aggression, depression, anxiety in social situations, and seizures, uncontrolled brain activity that is a serious life-threatening condition. Currently there is no cure for FXS, but some of the symptoms can be controlled with drugs. However, some of the drugs used can have unwanted side effects or the effectiveness of the drug may decrease over time. There is a great need to understand the underlying mechanisms of FXS symptoms as well as develop novel drugs to treat those symptoms.
Brain cells release chemicals called neurotransmitters to either excite or inhibit neighboring cells. This balance between excitation and inhibition allows for different regions of the brain to communicate with one another. In order for the brain to develop properly and to function in a healthy fashion, there has to be a balance between excitation and inhibition. In FXS there is an imbalance between excitatory and inhibitory neurotransmission that underlies the varying deficits. We are interested in the proteins that respond to the neurotransmitter that inhibits brain cell activity. The inhibitory neurotransmitter is called GABA and the protein it attaches to is called the GABAA receptor (GABAAR). When GABA binds to GABAARs, the receptor open up and allows an electrical current to pass through. This electrical signal stops the cell from becoming excited.
In FXS, the number of GABAARs in certain brain cells is decreased, which allows the nerve cells to become very excitable. The type of brain cells affected are located in areas of the brain known to be involved in memory, sleep, anxiety, and seizure activity. This lack of inhibition can cause the symptoms seen with FXS. Present treatments to overcome the reduced inhibition include drugs that boost the inhibitory electrical signal flowing through all GABAARs. However, this mechanism of action can make people feel drowsy or put them to sleep. Instead, we are proposing a new mechanism for treatment. We are proposing to use drugs, called neurosteroids, that are based on naturally occurring compounds that are normally made in the brain and apply them to increase the number of GABAARs in only the brain cells that have the deficit.
This work is innovative as we apply our novel findings on trafficking of GABAARs to the surface of cells. We have recently discovered that these naturally occurring neurosteroid compounds boost the numbers of GABAARs on the surface of brain cells and increase the inhibitory electrical signal. Rather than just increasing the weak inhibitory signal in FXS, our work seeks to boost GABAARs numbers back to normal and therefore overcome the deficit seen in FXS. In so doing, this can reverse many of the symptoms associated with FXS.
We will use a knockout mouse missing the gene that encodes for FMRP (Fmr1-/-), a widely validated model of the analogous human syndrome. We will use this mouse to examine (1) the biochemical changes to the GABAAR when cells are treated with neurosteroids, (2) the inhibitory electrical signal from brain cells that have received the neurosteroid treatment, and (3) the behavior of Fmr1-/- mice treated with neurosteroids.
In performing this study, we will gain a more in-depth knowledge on mechanisms that underlie reduced inhibition in the brains of individuals with FXS in particular and ASD in general. This will have an impact in the ASD research field as new pathways that influence receptor number will be explored. For individuals with ASD, this research will suggest a novel form of therapeutics that would treat their symptoms and kick start further drug development that targets not just the receptor but also how increase receptor numbers on the surface of the cell.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
