Mouse models of Angelman syndrome, a neurodevelopmental disorder, display different brain regional GABA A receptor alterations

Angelman syndrome is a severe neurodevelopmental disorder with cognitive impairment and neurological deficits. It results from a maternal deletion of human chromosome 15q11–13 containing two candidate genes E6–P ubiquitin-protein ligase (UBE3A) and GABA A receptor β3 subunit (GABRB3), the latter of which has been also linked to autism. To clarify the potential role of GABA A β3 subunit-containing inhibitory receptors in these disorders, we applied ligand autoradiography on brain sections from mice with inactivated GABRB3 or maternal UBE3A genes. Binding of GABA A receptor channel ([ 35S] t-butylbicyclophosphorothionate) and benzodiazepine ([ 3H]Ro 15–4513) site ligands was reduced in selected brain regions of the β3-deficient mice as compared to controls, while the UBE3A-deficient mice failed to show reduced GABA A receptors. The results, suggesting two different pathophysiological mechanisms, are in agreement with positron emission tomography results from Angelman syndrome patients of the corresponding genetic backgrounds.