Fig. 11.

Proposed pathway by which blocking glycine receptors reduces neuroinflammation and restores neurotransmission in cerebellum of hyperammonemic rats through an ADAM17-TNFR1-NF-kB pathway in Purkinje neurons. Glycine receptors are expressed mainly in Purkinje cells. In hyperammonemic rats, enhanced glycinergic neurotransmission leads to reduced membrane expression of ADAM17, resulting in increased surface expression and activation of TNFR1 and of the associated NF-kB pathway. This increases the expression in Purkinje neurons of TNFα, IL-1β, HMGB1, and glutaminase. Increased glutaminase activity leads to increased extracellular glutamate, which increases extracellular GABA. Increased extracellular glutamate and HMGB1 potentiate microglial activation. The effects of hyperammonemia are indicated by red arrows (↑). The effects of strychnine by the green symbol