Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain.
Anatomy and Human Embryology Department, Faculty of Medicine, University of Valencia, 46010, Valencia, Spain.
Mol Neurobiol. 2022 Jun;59(6):3431-3448. doi: 10.1007/s12035-022-02803-9. Epub 2022 Mar 23.
Rats with chronic hyperammonemia reproduce the cognitive and motor impairment present in patients with hepatic encephalopathy. It has been proposed that enhanced GABAergic neurotransmission in hippocampus may contribute to impaired learning and memory in hyperammonemic rats. However, there are no direct evidences of the effects of hyperammonemia on GABAergic neurotransmission in hippocampus or on the underlying mechanisms. The aims of this work were to assess if chronic hyperammonemia enhances the function of GABA receptors in hippocampus and to identify the underlying mechanisms. Activation of GABA receptors is enhanced in hippocampus of hyperammonemic rats, as analyzed in a multielectrode array system. Hyperammonemia reduces membrane expression of the GABA transporters GAT1 and GAT3, which is associated with increased extracellular GABA concentration. Hyperammonemia also increases gephyrin levels and phosphorylation of the β3 subunit of GABA receptor, which are associated with increased membrane expression of the GABA receptor subunits α1, α2, γ2, β3, and δ. Enhanced levels of extracellular GABA and increased membrane expression of GABA receptors would be responsible for the enhanced GABAergic neurotransmission in hippocampus of hyperammonemic rats. Increasing extracellular cGMP reverses the increase in GABA receptors activation by normalizing the membrane expression of GABA transporters and GABA receptors. The increased GABAergic neurotransmission in hippocampus would contribute to cognitive impairment in hyperammonemic rats. The results reported suggest that reducing GABAergic tone in hippocampus by increasing extracellular cGMP or by other means may be useful to improve cognitive function in hyperammonemia and in cirrhotic patients with minimal or clinical hepatic encephalopathy.
患有慢性高血氨症的大鼠重现了肝性脑病患者存在的认知和运动障碍。据推测，海马中增强的 GABA 能神经传递可能导致高氨血症大鼠学习和记忆受损。然而，目前尚无高氨血症对海马 GABA 能神经传递或潜在机制的直接影响的证据。本工作的目的是评估慢性高血氨症是否增强了海马中 GABA 受体的功能，并确定潜在的机制。在多电极阵列系统中分析表明，高氨血症大鼠海马中 GABA 受体的功能增强。高氨血症降低了 GABA 转运体 GAT1 和 GAT3 的膜表达，这与细胞外 GABA 浓度的增加有关。高氨血症还增加了 gephyrin 水平和 GABA 受体β3 亚基的磷酸化，这与 GABA 受体亚基 α1、α2、γ2、β3 和 δ 的膜表达增加有关。细胞外 GABA 的增强水平和 GABA 受体的膜表达增加是导致高氨血症大鼠海马中 GABA 能神经传递增强的原因。增加细胞外 cGMP 通过使 GABA 转运体和 GABA 受体的膜表达正常化来逆转 GABA 受体激活的增加。海马中增强的 GABA 能神经传递可能导致高氨血症大鼠的认知障碍。报告的结果表明，通过增加细胞外 cGMP 或通过其他手段增加 GABA 能神经传递可以改善高氨血症和最小或临床肝性脑病的肝硬化患者的认知功能。
