Mechanisms by which neuroinflammation modulates GABAergic neurotransmission in the hippocampus of hyperammonemic rats

Abstract

Hyperammonemia is a main contributor to cognitive impairment in patients with hepatic encephalopathy. Hyperammonemia-induced cognitive impairment is mediated by neuroinflammation and alteration of glutamatergic and GABAergic neurotransmission in hippocampus. Hyperammonemia enhances GABAergic neurotransmission in hippocampus but the role of neuroinflammation remains unknown. In cerebellum of hyperammonemic rats enhanced S1PR2-BDNF-TrkB pathway activation mediates enhancement of GABAergic neurotransmission. In hippocampus of hyperammonemic rats, the increase of IL-1β and Src kinase activation alters glutamatergic neurotransmission. The aims of this work were to assess if neuroinflammation is responsible for the enhanced GABAergic neurotransmission in hippocampus of hyperammonemic rats and to identify the underlying mechanisms. We used ex vivo hippocampal slices from control and hyperammonemic male rats and assessed the effects of blocking the S1PR2, the IL-1 receptor, TrkB or of inhibiting the protein kinases Src or PI3K on glutamate decarboxylases and GABA content and on membrane expression of GABA_A receptor, GABA transporters and chloride co-transporters. Blocking the S1PR2-IL-1β-Src-BDNF-TrkB-PI3K pathway at any of its steps reversed the reduced membrane expression of GABA transporters, which would increase extracellular GABA, and the increased membrane expression of most of the GABA_A receptor subunits analyzed, which also enhances GABAergic neurotransmission. This would be mediated by increasing the content of gephyrin and phosphorylation of the β3 subunit of GABA_A receptors. The identification of this pathway as the origin of the enhanced GABAergic neurotransmission provides several therapeutic targets to reverse cognitive impairment in hyperammonemia and hepatic encephalopathy and, likely, in other pathologies associated to neuroinflammation and enhanced GABAergic neurotransmission.