Figure 10.

Proposed pathway by which the neuroinflammation-induced enhanced activation of the TNFR1–S1PR2–CCL2–CCR2–BDNF–TrkB pathway enhances GABAergic neurotransmission in the cerebellum of hyperammonemic rats. Hyperammonemia-induced neuroinflammation increases the levels of BDNF in microglia through the activation of the TNFR1–S1PR2–CCL2–CCR2 pathway. Increased levels of BDNF enhance the activation of TrkB in Purkinje neurons, leading to increased levels of GABA-synthesizing enzymes GAD65 and GAD67, and of GABA. Enhanced TrkB activation also increases the membrane expression of the γ2, α2, and β3 subunits of GABAA receptors and of KCC2. Moreover, the enhanced activation of TrkB in activated astrocytes increases the membrane expression of GAT3 and of NKCC1, which also contributes to enhanced extracellular GABA. The increase in extracellular GABA and the membrane expression of GABAA receptors, and of KCC2 in Purkinje neurons results in enhanced GABAergic neurotransmission. All these changes in GABAergic neurotransmission are reversed by blocking TrkB or the TNFR1–SP1PR2–CCL2–CCR2–BDNF–TrkB pathway at any of its steps. The effects of hyperammonemia are indicated with red arrows (↑).