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 [C-11] 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.