Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus
Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus
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DOI：
10.1111/j.0953-816x.2003.03152.x
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发表时间：
2004-02-01
影响因子：
3.4
通讯作者：
Holmes, GL
中科院分区：
文献类型：
--
作者：
Khazipov, R;Khalilov, I;Holmes, GL
未成熟的大脑容易癫痫发作，但其潜在机制尚不清楚。我们探讨了这一假设，即增加癫痫发作的易感性在早期发展是由于兴奋作用的GABA。使用非侵入性的细胞外场电位和细胞贴附记录在CA 3的Sprague-Dawley大鼠海马脑片，我们比较了三个参数的发育变化：GABA的兴奋作用，存在的不成熟模式的巨大去极化电位（GDPs）和癫痫样活动的严重程度产生的高钾。GABA（A）受体激动剂异谷瓦辛增加新生儿脑片中CA 3锥体细胞的放电，同时抑制成人脑片中的活动。GABA（A）信号从兴奋到抑制的转换发生在出生后第13.5 +/- 0.4天（P）。在P12.7 +/- 0.3之前，田间GDP以自发群体爆发的形式存在。高钾（8.5 mM）在P7-16（P11.3 +/- 0.4时达到峰值）时在35%的切片中诱导了类似癫痫的事件（SLE），但仅在该年龄之前和之后诱导了发作间期活动。GABA（A）受体拮抗剂荷包牡丹碱可降低或完全阻断SLE的频率，并诱导发作间期的阵挛样活动，伴随着频率的降低，但在群体尖峰的幅度增加。在具有发作间期活动的切片中，荷包牡丹碱通常在所有年龄引起大幅度的发作间期阵挛样活动;在P5-16大鼠的切片中，在荷包牡丹碱应用开始时，通常先有一个SLE。这些结果表明，在未成熟的海马，GABA发挥双重（兴奋性和抑制性）的行动和GABA的行动中的兴奋性成分可能有助于增加兴奋性在早期发展。
The immature brain is prone to seizures but the underlying mechanisms are poorly understood. We explored the hypothesis that increased seizure susceptibility during early development is due to the excitatory action of GABA. Using noninvasive extracellular field potential and cell-attached recordings in CA3 of Sprague-Dawley rat hippocampal slices, we compared the developmental alterations in three parameters: excitatory actions of GABA, presence of the immature pattern of giant depolarizing potentials (GDPs) and severity of epileptiform activity generated by high potassium. The GABA(A) receptor agonist isoguvacine increased firing of CA3 pyramidal cells in neonatal slices while inhibiting activity in adults. A switch in the GABA(A) signalling from excitation to inhibition occurred at postnatal day (P) 13.5 +/- 0.4. Field GDPs were present in the form of spontaneous population bursts until P12.7 +/- 0.3. High potassium (8.5 mM) induced seizure-like events (SLEs) in 35% of slices at P7-16 (peak at P11.3 +/- 0.4), but only interictal activity before and after that age. The GABA(A) receptor antagonist bicuculline reduced the frequency or completely blocked SLEs and induced interictal clonic-like activity accompanied by a reduction in the frequency but an increase in the amplitude of the population spikes. In slices with interictal activity, bicuculline typically caused a large amplitude interictal clonic-like activity at all ages; in slices from P5-16 rats it was often preceded by one SLE at the beginning of bicuculline application. These results suggest that, in the immature hippocampus, GABA exerts dual (both excitatory and inhibitory) actions and that the excitatory component in the action of GABA may contribute to increased excitability during early development.