Hyperammonemia Increases GABAergic Tone in the Cerebellum but Decreases It in the Rat Cortex
Hyperammonemia Increases GABAergic Tone in the Cerebellum but Decreases It in the Rat Cortex
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DOI：
10.1053/j.gastro.2008.12.057
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发表时间：
2009-04-01
期刊：
影响因子：
29.4
通讯作者：
Felipo, Vicente
中科院分区：
文献类型：
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作者：
Cauli, Omar;Mansouri, Mohammad T.;Felipo, Vicente
背景和目的：GABAA 受体调节谷氨酸-一氧化氮-鸟苷 3',5'-环单磷酸 (cGMP) 途径的功能，该途径在高氨血症大鼠的小脑中减少。有人提出，高氨血症诱导的γ-氨基丁酸“（GABAergic）音调”增加有助于肝性脑病（HE）的发病机制，尽管尚未在动物模型中进行体内评估。我们研究了大鼠慢性高氨血症是否会增加小脑和/或大脑皮层的 GABA 能张力，以及这种增加是否会导致认知障碍。方法：我们用荷包牡丹碱阻断大鼠的GABA(A)受体，并分析该通路在小脑中的功能以及对学习能力的影响。结果：高血氨血症增加了大鼠小脑中的 GABA 能张力，但降低了大脑皮层中的 GABA 能张力。高氨血症大鼠小脑中 GABA 能张力的增加可能是由细胞外 GABA 的增加引起的。四氢脱氧皮质酮（一种增强 GABA(A) 受体激活的神经类固醇）；或GABA(A)受体的α1、α6和γ2亚基的量。皮层中观察到的 GABA 能性降低可能是由于 GABA(A) 受体 δ 和 γ 2 亚基数量减少或孕烯醇酮水平增加（5 倍）所致，后者选择性地减少含有 α 4 亚基的 GABA(A) 受体的激活（在皮层中广泛表达，但在小脑中不表达）。荷包牡丹碱治疗可使高氨血症大鼠的 GABA 能正常化，并恢复由 N-甲基-D-天冬氨酸受体激活和学习能力诱导的 cGMP 增加。结论：小脑 GABA 能张力增加导致高氨血症大鼠认知障碍。
Background & Aims: GABAA receptors modulate the function of the glutamate-nitric oxide-guanosine 3',5'-cyclic monophosphate (cGMP) pathway, which is reduced in cerebellum in hyperammonemic rats. It has been proposed that hyperammonemia-induced increases in gamma-aminobutyric acid "(GABAergic) tone" contribute to the pathogenesis of hepatic encephalopathy (HE), although this has not been assessed in vivo in animal models. We studied whether chronic hyperammonemia in rats increases GABAergic tone in the cerebellum and/or cerebral cortex and whether this increase contributes to cognitive impairment. Methods: We blocked GABA(A) receptors of rats with bicuculline and analyzed the function of this pathway in cerebellum and effects on learning ability. Results: Hyperanimonemia increased GABAergic tone in cerebellum but decreased it in the cerebral cortex of rats. Increased GABAergic tone in the cerebellum of rats with hyperammonemia could have been caused by increases in extracellular GABA; tetrahydrodeoxy-corticosterone (a neurosteroid that enhances GABA(A) receptor activation); or amounts of the alpha 1, alpha 6, and gamma 2 subunits of GABA(A) receptors. The decrease in GABAergic tone observed in the cortex could have resulted from the reduced amount of GABA(A) receptors delta and gamma 2 subunits or increased levels of pregnanolone (5-fold), which selectively reduces activation of GABA(A) receptors that contain alpha 4 subunits (widely expressed in cortex but not in cerebellum). Treatment with bicuculline normalized GABAergic tone and restored the increase in cGMP that was induced by activation of N-metbyl-D-aspartate receptors and learning ability in hyperammonemic rats. Conclusions: Increased GABAergic tone in the cerebellum contributes to cognitive impairment in hyperammonemic rats.