Sperk G, Schwarzer C, Tsunashima K, Kandlhofer S
Department of Pharmacology, University of Innsbruck, Austria.
Epilepsy Res. 1998 Sep;32(1-2):129-39. doi: 10.1016/s0920-1211(98)00046-1.
The GABA(A) receptor is a ligand gated chloride channel consisting of five membrane spanning proteins for which 13 different genes have been identified in the mammalian brain. The present review summarizes recent work from our laboratory on the characterization of the immunocytochemical distribution of these GABA(A) receptor subunits in the rat brain and changes in immunoreactivity and mRNA expression after kainic acid-induced status epilepticus. A heterogeneous distribution of immunoreactive GABA(A) receptor subunits was observed. The most abundant ones were: alpha1, alpha2, alpha4, alpha5, beta2, beta3, gamma2, and delta. Alpha1, beta2, and gamma2 were about equally distributed in all subfields of the hippocampus; alpha4- and delta-subunits were preferentially found in the dentate molecular layer and in CA1; alpha2 was localized to the dentate molecular layer and CA3; alpha5 was found in the dendritic areas of CA1 to CA3; and beta1 was preferentially seen in CA2. Alpha1, beta2, gamma2 and delta were highly concentrated in interneurons. Kainic acid-induced seizures caused acute and chronic changes in the expression of mRNAs and immunoreactive proteins. Acute changes included decreases in alpha2, alpha5, beta1, beta3, gamma2 and delta mRNA levels (by about 25-50%), accompanied by increases (by about 50%) in alpha1, alpha4, and beta2 messages in granule cells (after 6-12 h). Chronic changes, characterized by losses in mRNA and immunoreactive proteins in CA1 and CA3, are undoubtedly due to seizure-related cell damage. However, compensatory expression of alpha2 and beta3 subunits, especially in CA3b/c, was observed. Furthermore, increases in mRNAs and immunoreactive proteins were seen for alpha1, alpha2 alpha4, beta1, beta2, beta3 and gamma2 in granule cells and in the molecular layer of the dentate gyrus at 7-30 days after kainic acid injection. The changes in the expression of GABA(A) receptor subunits, observed in practically all hippocampal subfields, may reflect altered GABA-ergic transmission during development of the epileptic syndrome. Increased expression of GABA(A) receptor subunits in the dendritic field of granule cells and CA3 suggest that GABA-ergic inhibition may be augmented at these levels. However, the lasting preservation of alpha1-, beta2-, and gamma2-subunits in interneurons could provide a basis for augmented inhibition of GABA-ergic interneurons, leading to net disinhibition.
GABA(A)受体是一种配体门控氯离子通道，由五个跨膜蛋白组成，在哺乳动物大脑中已鉴定出13种不同的基因。本综述总结了我们实验室最近关于大鼠脑中这些GABA(A)受体亚基免疫细胞化学分布特征以及海藻酸诱导癫痫持续状态后免疫反应性和mRNA表达变化的研究工作。观察到免疫反应性GABA(A)受体亚基的分布不均一。最丰富的亚基有：α1、α2、α4、α5、β2、β3、γ2和δ。α1、β2和γ2在海马的所有亚区中分布大致相等；α4和δ亚基优先存在于齿状分子层和CA1区；α2定位于齿状分子层和CA3区；α5存在于CA1至CA3的树突区域；β1优先见于CA2区。α1、β2、γ2和δ在中间神经元中高度富集。海藻酸诱导的癫痫发作导致mRNA和免疫反应性蛋白表达的急性和慢性变化。急性变化包括α2、α5、β1、β3、γ2和δ mRNA水平下降（约25%-50%），同时颗粒细胞中α1、α4和β2的信息增加（约50%）（6-12小时后）。慢性变化表现为CA1和CA3区mRNA和免疫反应性蛋白的丢失，这无疑是由于癫痫发作相关的细胞损伤所致。然而，观察到α2和β3亚基的代偿性表达，尤其是在CA3b/c区。此外，在注射海藻酸后7-30天，颗粒细胞和齿状回分子层中α1、α2、α4、β1、β2、β3和γ2的mRNA和免疫反应性蛋白增加。在几乎所有海马亚区观察到的GABA(A)受体亚基表达变化，可能反映了癫痫综合征发展过程中GABA能传递的改变。颗粒细胞和CA3树突区域中GABA(A)受体亚基表达的增加表明，在这些水平上GABA能抑制作用可能增强。然而，中间神经元中α1、β2和γ2亚基的持续保留可能为增强对GABA能中间神经元的抑制提供基础，导致净去抑制。
