title: Altered GABA(A) receptor subunit expression and pharmacology in human Angelman syndrome cortex.
abstract: The neurodevelopmental disorder Angelman syndrome is most frequently caused by deletion of the maternally derived chromosome 15q11-q13 region, which includes not only the causative UBE3A gene, but also the beta(3)-alpha(5)-gamma(3) GABA(A) receptor subunit gene cluster. GABAergic dysfunction has been hypothesized to contribute to the occurrence of epilepsy and cognitive and behavioral impairments in this condition. In the present study, analysis of GABA(A) receptor subunit expression and pharmacology was performed in cerebral cortex from four subjects with Angelman syndrome and compared to that from control tissue. The membrane fraction of frozen postmortem neocortical tissue was isolated and subjected to quantitative Western blot analysis. The ratios of beta(3)/beta(2) and alpha(5)/alpha(1) subunit protein expression in Angelman syndrome cortex were significantly decreased when compared with controls. An additional membrane fraction was injected into Xenopus oocytes, resulting in incorporation of the brain membrane vesicles with their associated receptors into the oocyte cellular membrane. Two-electrode voltage-clamp analysis of GABA(A) receptor currents was then performed. Studies of GABA(A) receptor pharmacology in Angelman syndrome cortex revealed increased current enhancement by the alpha(1)-selective benzodiazepine-site agonist zolpidem and by the barbiturate phenobarbital, while sensitivity to current inhibition by zinc was decreased. GABA(A) receptor affinity and modulation by neurosteroids were unchanged. This shift in GABA(A) receptor subunit expression and pharmacology in Angelman syndrome is consistent with impaired extrasynaptic but intact to augmented synaptic cortical GABAergic inhibition, which could contribute to the epileptic, behavioral, and cognitive phenotypes of the disorder.
authors.affiliation: Seattle Children's Research Institute, Center for Integrative Brain Research, Seattle, WA 98101, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Roden
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Peugh
authors.forename: Laura A
authors.initials: LA
authors.lastname: Jansen
mesh_terms: D000293:Adolescent; D000328:Adult; D017204:Angelman Syndrome / Q000473:pathology*; D000818:Animals; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism*; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D010634:Phenobarbital / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018757:GABA Modulators; D021122:Protein Subunits; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D010634:Phenobarbital