RAPID DECLINE OF GABA(A) RECEPTOR SUBUNIT MESSENGER-RNA EXPRESSION IN HIPPOCAMPUS FOLLOWING TRANSIENT CEREBRAL-ISCHEMIA IN THE GERBIL
RAPID DECLINE OF GABA(A) RECEPTOR SUBUNIT MESSENGER-RNA EXPRESSION IN HIPPOCAMPUS FOLLOWING TRANSIENT CEREBRAL-ISCHEMIA IN THE GERBIL
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DOI：
10.1002/hipo.450030412
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发表时间：
1993-10-01
期刊：
影响因子：
3.5
通讯作者：
SCHWARTZ, RD
中科院分区：
文献类型：
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作者：
LI, HL;SIEGEL, RE;SCHWARTZ, RD
抑制性神经传递可能在短暂性脑缺血后神经元变性中发挥重要作用。本文研究了短暂性前脑缺血对沙土鼠海马GABA（A）受体系统的影响。沙鼠进行5分钟的双侧颈动脉闭塞，并在不同的时间超过4天后再灌注处死。缺血4天后，海马CA 1区锥体细胞大量丢失。在缺血后的任何时间，在海马CA 3锥体细胞、齿状回颗粒细胞层和丘脑腹后内侧核和腹后外侧核中均未检测到细胞丢失。通过原位杂交组织化学对脑切片的检查显示，GABA（A）受体α 1和β 2亚单位mRNA表达的变化发生在再灌注开始后的两个阶段。早期（快速）发生在再灌注后的前4小时内。海马CA 1和CA 3区锥体细胞层和齿状回颗粒细胞层的mRNA表达在阻断后1小时内显著降低（达25%）。这些区域中mRNA的表达持续降低4小时（高达43%）。在第二阶段，即再灌注后4至12小时之间开始，mRNA表达开始恢复到CA 3海马和齿状回的对照水平。然而，在接下来的3天中，两种mRNA的表达在CA 1锥体细胞层中继续缓慢下降（高达85%），伴随着CA 1锥体细胞的变性。丘脑腹后内侧核或腹后外侧核的mRNA表达与对照值相似。为了确定GABA（A）受体分布的变化是否会导致受体亚基mRNA表达的变化，我们还测量了[S-35]叔丁基双环硫代磷酸酯与GABA（A）受体氯离子通道的结合。再灌注后1 - 4天，CA 1锥体细胞（定向层、放射层和腔隙-分子层）的树突状区域中的叔丁基双环硫代磷酸酯[S-35]结合率降低，但锥体细胞体层中的结合率未降低。这些结果表明，GABA（A）受体亚基mRNA的表达在CA 1锥体细胞变性和GABA（A）受体丢失之前就已降低。目前，尚不清楚缺血损伤后早期mRNA表达的丧失是否导致GABA（A）受体的功能缺陷。如果是这样的话，GABA神经传递的损失可能有助于脑缺血后神经元变性的发展。存活细胞中正常GABA神经传递的维持可以解释它们对缺血诱导的神经元死亡的抵抗。
Inhibitory neurotransmission may play an important role in neuronal degeneration following transient cerebral ischemia. We studied the effect of transient forebrain ischemia on the GABA(A) receptor system in the gerbil hippocampus. Gerbils were subjected to 5 minutes of bilateral carotid occlusion and were sacrificed at various times over 4 days following reperfusion. There was a substantial loss of pyramidal cells in the CA1 area of the hippocampus 4 days following ischemia. No cell loss was detected in CA3 pyramidal cells of the hippocampus, granule cell layer of the dentate gyrus, and ventroposterior medial and ventroposterior lateral nuclei of the thalamus at any time following ischemia. Examination of brain slices by in situ hybridization histochemistry revealed that a change in expression of the GABA(A) receptor alpha1 and beta2 subunit mRNAs occurred in two phases following onset of reperfusion. The early phase (rapid) occurred within the first 4 hours following reperfusion. The expression of mRNAs significantly decreased (up to 25%) within 1 hour after occlusion in CA1 and CA3 pyramidal cell layers of the hippocampus and in the granule cell layer of the dentate gyrus. The expression of the mRNAs in these regions continued to decrease for 4 hours (up to 43%). In the second phase, which began between 4 and 12 hours following reperfusion, mRNA expression started to return to control levels in CA3 hippocampus and in the dentate. However, expression of both mRNAs continued to decline slowly in the CA1 pyramidal cell layer (up to 85%) over the next 3 days, concomitantly with degeneration of the CA1 pyramidal cells. Expression of mRNAs in the ventroposterior medial or ventroposterior lateral nuclei of the thalamus was similar to control values. To determine if a change in GABA(A) receptor distribution paralleled changes in receptor subunit mRNA expression, we also measured the binding of [S-35]t-butylbicyclophosphorothionate to GABA(A) receptor chloride channels. The t-butylbicyclophosphorothionate [S-35] binding decreased between 1 and 4 days after reperfusion in the dendritic fields of CA1 pyramidal cells (strata oriens, radiatum, and lacunosum-moleculare) but not in the pyramidal cell body layer. These results indicate that expression of GABA(A) receptor subunit mRNAs decrease well before CA1 pyramidal cell degeneration and loss of GABA(A) receptors. At present, it is not clear if an early loss of mRNA expression after an ischemic insult leads to a functional defect in GABA(A) receptors. If so, a loss of GABA neurotransmission may contribute to the development of neuronal degeneration following cerebral ischemia. The maintenance of normal GABA neurotransmission in surviving cells may explain their resistance to ischemia-induced neuronal death.