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.
Sci Rep. 2016 Aug 26;6:31928. doi: 10.1038/srep31928.
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.
超过一半的癫痫患儿会自发缓解，但具体机制尚不清楚。由于突触外α4βδ GABAA 受体（GABARs）的表达，青春期雌性小鼠的 GABA 能抑制作用增强。因此，我们使用高钾（8.5mM）癫痫模型来测试这些受体在调节 CA1 海马区癫痫样放电中的作用。在青春期前（28-32 日龄）和青春期（35-44 日龄）雌性野生型或α4-/-小鼠的海马区记录自发场电位。通过海岸线长度（一种衡量爆发强度的指标）来评估。8.5mM K+ 在超过 60%的青春期前切片中诱导癫痫样放电，但仅在 7%的青春期切片中诱导，其中海岸线长度减少了 70%（P=0.04）。然而，α4-/- 小鼠中并未观察到青春期癫痫样放电减少，表明α4βδ GABARs 是青春期癫痫样活动减少的原因。THIP 或 DS2 的给药可选择性增加α4βδ 电流，减少青春期 8.5mM K+中的活性，而阻断α5-GABARs 则没有影响。在 8.5mM K+中，GABA 能电流具有去极化作用，但具有抑制作用，这表明α4βδ 和 α5-GABARs 的作用机制不同，它们表现出不同的极性依赖性脱敏。这些数据表明，α4βδ GABARs 在青春期具有抗惊厥作用。
