Andrea Palomares-Rodriguez, Yaiza M Arenas, Vicente Felipo
Hyperammonemic rats show neuroinflammation and enhanced GABAergic neurotransmission in cerebellum. Treating hyperammonemic rats with compounds that reduce GABAA 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 GABAA receptors activation contributes to activation of microglia, which releases pro-inflammatory factors that activate astrocytes, and that blocking GABAA receptors with bicuculline will reverse these effects. The first aim was to characterize the effects of reducing GABAA 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 GABAA 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 GABAA 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 GABAA receptors with bicuculline, indicating that are triggered by GABAA receptors over-activation. These data support that enhanced GABAA receptors activation in cerebellum induces pro-inflammatory effects in hyperammonemic rats and anti-inflammatory effects in control rats.