Abstract
Over the last several years, evidence has accumulated that the GABAA 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 GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET) and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA 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 GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.
Highlights
Fragile X syndrome patients show mild to severe cognitive impairment and have a distinct physical appearance [1]
All volunteers showed a single band in the unaffected size range for FXS, indicating absence of fragile X syndrome or any of the premutation related disorders
The non-displaceable binding potential (BPND; the free plus non- bound concentration in brain), which reflects the availability of GABAA receptors, showed a significant mean decrease of 10% (BPND group_AVG = 3.31, BPND HV = 3.48, BPND fragile X patients (FXP) = 3.14; p = 0.036; with z-scores ranging from -0.36 to 1.41 for the controls and -1.83 to 1.20 for the patients) in total grey matter binding of flumazenil in FXS patients when compared to the controls (Figs 1 and 2; S1 Fig)
Summary
Fragile X syndrome patients show mild to severe cognitive impairment and have a distinct physical appearance [1]. Many behavioral problems, such as hyperactivity, aggression, social anxiety, impaired sensorimotory gating and autistic-like features, are associated with the syndrome [2]. An increased risk of epileptic seizures is reported [3]. PET Scans Demonstrate GABA Receptor Deficiencies in Fragile X Patients collection and analysis, decision to publish, or preparation of the manuscript
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