|Treatment of fragile X syndrome via the GABAA receptor
by Frank Kooy, 9/30/2008
Absence of a single protein, FMRP, in fragile X patients leads to a cascade of molecular events in brain cells. To find out which other genes are involved the clinical symptoms, we have been looking for genes that are differentially expressed in fragile X syndrome. One of the genes specifically underexpressed is part of the GABAA receptor. As GABAA receptors are the main inhibitory receptors in the brain, involved in processes like anxiety, mood swings, sleep and cognition, processes also disturbed in fragile X patients, we followed up on this finding. In subsequent studies, we demonstrated abnormalities in expression levels of multiple parts of the GABAA receptor, both in the mouse model and in the fly model, indicating underexpression is an evolutionary conserved hallmark of fragile X syndrome. Our case for involvement of the GABAergic system in fragile X is supported by independent findings from other groups.
The purpose of this grant is twofold: first, we want to understand why and how absence of the fragile X protein results in underexpression of the GABA system. Second, we want to investigate whether drugs that work on the GABA system are able to influence the phenotype of the fragile X mouse model.
During the first year of our study, we analyzed the relative expression of many genes that are responsible for GABA synthesis, transport, clustering and degradation. Essentially all of these genes were under expressed in the fragile X syndrome, strengthening our hypothesis that the entire GABA system is down regulated in the disorder. In current animal experiments, we are now investigating whether drugs that reactivate the GABA system are able to correct some of the symptoms observed in patients, including epilepsy, hyper activity and anxiety. In initial experiments, we already verified that GABAergic drugs such as the neurosteroid alphaxolone are still effective in the knockout mice.
A second breakthrough in the first year of this project was the observation that the GABA receptor mRNAs that are down regulated are a part of the FMRP-mRNP complex. This means that FMRP binds GABA RNAs, possibly explaining why the GABAergic system is down regulated in fragile X syndrome. Planned experiments will follow up on this finding and aim to unravel the precise mechanism of GABAergic down regulation.