Molnar L R, Fleming W W, Taylor D A
Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9223, USA.
J Pharmacol Exp Ther. 2000 Dec;295(3):1258-66.
The genetically epilepsy-prone rat (GEPR) is a unique animal model of seizure predisposition with substrains (i.e., GEPR-NE, GEPR-3, and GEPR-9) that exhibit different seizure patterns in response to the same stimulus. Among many deficits identified in these animals, reduced responses to GABA(A) receptor agonists have been described in several brain regions of the GEPR-9. However, few studies have quantitatively analyzed this difference in responsiveness or have examined and compared the responsiveness of GEPR-3 neurons with the other strains. Using intracellular recording, we determined and compared the responsiveness of Purkinje neurons from GEPR-3 animals with those of control (both Sprague-Dawley and GEPR-NE) and GEPR-9 rats at different developmental ages. In GEPR-9 animals, the EC(50) value for GABA and muscimol was shifted 3-fold to the right, with no reduction in maximum. In contrast, GEPR-3 animals showed a significant reduction in the maximum hyperpolarizing response to only GABA and muscimol with no change in the EC(50) values. Responsiveness to glutamate, aspartate, norepinephrine, and diazepam was unchanged in both strains, indicating that the change in responsiveness was highly selective for GABA(A) receptor agonists. Changes in responsiveness in animals <15 days of age suggests that deficits in GABAergic function exist before the development of seizure susceptibility. In addition, the data are the first to reveal that the GEPR-3 and GEPR-9 exhibit different changes in GABA(A) receptor function and may provide significant insight into the cellular mechanism underlying differences between these two strains.
遗传性癫痫易感大鼠（GEPR）是一种独特的癫痫易感性动物模型，其亚系（即GEPR-NE、GEPR-3和GEPR-9）在受到相同刺激时会表现出不同的癫痫发作模式。在这些动物中发现的许多缺陷中，GEPR-9的几个脑区对GABA(A)受体激动剂的反应性降低已有报道。然而，很少有研究对这种反应性差异进行定量分析，也很少有研究检查和比较GEPR-3神经元与其他品系的反应性。我们使用细胞内记录法，测定并比较了不同发育年龄的GEPR-3动物的浦肯野神经元与对照动物（斯普拉格-道利大鼠和GEPR-NE）以及GEPR-9大鼠的反应性。在GEPR-9动物中，GABA和蝇蕈醇的半数有效浓度（EC(50)）值向右移动了3倍，最大反应性没有降低。相比之下，GEPR-3动物仅对GABA和蝇蕈醇的最大超极化反应显著降低，而EC(50)值没有变化。两种品系对谷氨酸、天冬氨酸、去甲肾上腺素和地西泮的反应性均未改变，这表明反应性的变化对GABA(A)受体激动剂具有高度选择性。15日龄以下动物反应性的变化表明，在癫痫易感性发展之前就存在GABA能功能缺陷。此外，这些数据首次揭示了GEPR-3和GEPR-9在GABA(A)受体功能上表现出不同的变化，可能为这两个品系之间差异的细胞机制提供重要见解。
