Blocking GABAA receptors with bicuculline reverses microglia and astrocytes activation and enhanced activation of the TNFα-TNFR1-S1PR2-CCl2-CCR2-BDNF-TrkB pathway in cerebellum of hyperammonemic rats

Hyperammonemic rats show neuroinflammation and enhanced GABAergic neurotransmission in cerebellum. Treating hyperammonemic rats with compounds that reduce GABA A receptors activation reduces some aspects of neuroinflammation. How GABAergic neurotransmission affects glial activation and the mechanisms involved are not clear. We hypothesized that, in cerebellum of hyperammonemic rats, enhanced GABA A receptors activation contributes to activation of microglia, which releases pro-inflammatory factors that activate astrocytes, and that blocking GABA A receptors with bicuculline will reverse these effects. The first aim was to characterize the effects of reducing GABA A receptors activation with bicuculline in cerebellum of hyperammonemic rats on microglia and astrocytes activation. Neuroinflammation enhances GABAergic neurotransmission in cerebellum of hyperammonemic rats by activating the TNFα-TNFR1-S1PR2-CCl2-CCR2-BDNF-TrkB pathway and the TNFα-TNFR1-NFkB-glutaminase-GAT3 pathway. The second aim of this work was to assess if GABA A receptors over-activation contributes to enhance activation of these pathways by analyzing if it is reversed by bicuculline. Hyperammonemia induces pro-inflammatory microglia activation, increasing NFκB, MAPK p38, STAT3, TNFα and glutaminase in microglia and TNFα, IL-1α and C1q which induce astrocytes activation. Enhanced GABA A receptors activation also contributes to activate the TNFα-TNFR1-S1PR2-CCl2-CCR2-BDNF-TrkB, and TNFα-TNFR1-NFkB-glutaminase-GAT3 pathways. All these effects are reversed in cerebellar slices from hyperammonemic rats by blocking GABA A receptors with bicuculline, indicating that are triggered by GABA A receptors over-activation. These data support that enhanced GABA A receptors activation in cerebellum induces pro-inflammatory effects in hyperammonemic rats and anti-inflammatory effects in control rats.