title: Pubertal Expression of α4βδ GABAA Receptors Reduces Seizure-Like Discharges in CA1 Hippocampus.
abstract: More than half of children with epilepsy outgrow their seizures, yet the underlying mechanism is unknown. GABAergic inhibition increases at puberty in female mice due to expression of extrasynaptic α4βδ GABAA receptors (GABARs). Therefore, we tested the role of these receptors in regulating seizure-like discharges in CA1 hippocampus using a high K(+) (8.5 mM) seizure model. Spontaneous field potentials were recorded from hippocampus of pre-pubertal (~28-32 PND) and pubertal (~35-44 PND) female wild-type or α4-/- mice. The coastline length, a measure of burst intensity, was assessed. 8.5 mM K(+) induced seizure-like discharges in over 60% of pre-pubertal slices, but only in 7% of pubertal slices, where the coastline length was reduced by 70% (P = 0.04). However, the pubertal decrease in seizure-like discharges was not seen in the α4-/-, implicating α4βδ GABARs as the cause of the decreased seizure-like activity during puberty. Administration of THIP or DS2, to selectively increase α4βδ current, reduced activity in 8.5 mM K(+) at puberty, while blockade of α5-GABARs had no effect. GABAergic current was depolarizing but inhibitory in 8.5 mM K(+), suggesting a mechanism for the effects of α4βδ and α5-GABARs, which exhibit different polarity-dependent desensitization. These data suggest that α4βδ GABARs are anti-convulsant during adolescence.
authors: Department of Physiology &Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
authors: Lie
authors: L
authors: Yang
authors: Department of Physiology &Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.|Department of Biomedical Engineering, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 30070, China.
authors: Hui
authors: H
authors: Shen
authors: Department of Physiology &Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.|Department of Neurology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.|Department of Neurology, Kings County Hospital, Brooklyn, NY 11203, USA.
authors: Lisa R
authors: LR
authors: Merlin
authors: Department of Physiology &Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
authors: Sheryl S
authors: SS
authors: Smith
mesh_terms: D000367:Age Factors; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000503:physiopathology*; D002414:Cations, Monovalent; D005071:Evoked Potentials; D005260:Female; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D011188:Potassium; D011963:Receptors, GABA-A / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D012741:Sexual Maturation / Q000502:physiology*
chemical_list: C000609924:4-chloro-N-(2-(2-thienyl)imidazo(1,2-a)pyridin-3-yl)benzamide; D001549:Benzamides; D002414:Cations, Monovalent; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; D007555:Isoxazoles; D011963:Receptors, GABA-A; C015542:gaboxadol; D011188:Potassium