Positron Emission Tomography (PET) Quantification of GABAA Receptors in the Brain of Fragile X Patients

Over the last several years, evidence has accumulated that the GABA A receptor is compromised in animal models for fragile X syndrome (FXS), a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABA A receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABA A receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET) and [ 11 C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABA A receptors. We measured regional GABA A receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABA A receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABA A receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABA A receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABA A receptor is a potential target for rational pharmacological treatment of fragile X syndrome.