Altered GABAA receptor subunit expression and pharmacology in human Angelman syndrome cortex

William H. Roden, Lindsey D. Peugh, Laura A. Jansen

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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 β353 GABAA 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 GABAA 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 β32 and α51 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 GABAA receptor currents was then performed. Studies of GABAA receptor pharmacology in Angelman syndrome cortex revealed increased current enhancement by the α1-selective benzodiazepine-site agonist zolpidem and by the barbiturate phenobarbital, while sensitivity to current inhibition by zinc was decreased. GABAA receptor affinity and modulation by neurosteroids were unchanged. This shift in GABAA 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.

Original languageEnglish
Pages (from-to)167-172
Number of pages6
JournalNeuroscience Letters
Issue number3
StatePublished - Oct 2010


  • Angelman syndrome
  • Cerebral cortex
  • Electrophysiology
  • Epilepsy
  • GABA-A receptor
  • Human
  • Pharmacology


Dive into the research topics of 'Altered GABAA receptor subunit expression and pharmacology in human Angelman syndrome cortex'. Together they form a unique fingerprint.

Cite this