Voor het Angelman Syndroom

pdf Altered GABAA Receptor Subunit Expression and Pharmacology in Human Angelman Syndrome Cortex Populair

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Roden WH 2010 Neurosci Lett e-pub.pdf

The neurodevelopmental disorder Angelman syndrome is most frequently causedby deletion of the maternally-derived chromosome 15q11-q13 region, which includes notonly the causative UBE3A gene, but also the beta3-alpha 5-gamma3 GABAA receptor subunit genecluster. GABAergic dysfunction has been hypothesized to contribute to the occurrence ofepilepsy and cognitive and behavioral impairments in this condition. In the present study,analysis of GABAA receptor subunit expression and pharmacology was performed incerebral cortex from four subjects with Angelman syndrome and compared to that fromcontrol tissue. The membrane fraction of frozen postmortem neocortical tissue wasisolated and subjected to quantitative Western blot analysis. The ratios of beta3/beta2 and alpha 5/alpha 1subunit protein expression in Angelman syndrome cortex were significantly decreasedwhen compared with controls. An additional membrane fraction was injected intoXenopus oocytes, resulting in incorporation of the brain membrane vesicles with theirassociated receptors into the oocyte cellular membrane. Two-electrode voltage clampanalysis of GABAA receptor currents was then performed. Studies of GABAA receptorpharmacology in Angelman syndrome cortex revealed increased current enhancement bythe alpha 1-selective benzodiazepine site agonist zolpidem and by the barbituratephenobarbital, while sensitivity to current inhibition by zinc was decreased. GABAAreceptor affinity and modulation by neurosteroids were unchanged. This shift in GABAAreceptor subunit expression and pharmacology in Angelman syndrome is consistent withimpaired extrasynaptic but intact to augmented synaptic cortical GABAergic inhibition,which could contribute to the epileptic, behavioral, and cognitive phenotypes of thedisorder.

W.H. Roden, L.D. Peugh, L.A. Jansen

Neuroscience Letters (2010), doi:10.1016/j.neulet.2010.08.001