Hyperammonemia Increases GABAergic Tone in the Cerebellum but Decreases It in the Rat Cortex

Background & Aims: GABAA receptors modulate the function of the glutamate-nitric oxide-guanosine 3',5'-cyclic monophosphate (cGMP) pathway, which is reduced in cerebellum in hyperammonemic rats. It has been proposed that hyperammonemia-induced increases in gamma-aminobutyric acid "(GABAergic) tone" contribute to the pathogenesis of hepatic encephalopathy (HE), although this has not been assessed in vivo in animal models. We studied whether chronic hyperammonemia in rats increases GABAergic tone in the cerebellum and/or cerebral cortex and whether this increase contributes to cognitive impairment. Methods: We blocked GABA(A) receptors of rats with bicuculline and analyzed the function of this pathway in cerebellum and effects on learning ability. Results: Hyperanimonemia increased GABAergic tone in cerebellum but decreased it in the cerebral cortex of rats. Increased GABAergic tone in the cerebellum of rats with hyperammonemia could have been caused by increases in extracellular GABA; tetrahydrodeoxy-corticosterone (a neurosteroid that enhances GABA(A) receptor activation); or amounts of the alpha 1, alpha 6, and gamma 2 subunits of GABA(A) receptors. The decrease in GABAergic tone observed in the cortex could have resulted from the reduced amount of GABA(A) receptors delta and gamma 2 subunits or increased levels of pregnanolone (5-fold), which selectively reduces activation of GABA(A) receptors that contain alpha 4 subunits (widely expressed in cortex but not in cerebellum). Treatment with bicuculline normalized GABAergic tone and restored the increase in cGMP that was induced by activation of N-metbyl-D-aspartate receptors and learning ability in hyperammonemic rats. Conclusions: Increased GABAergic tone in the cerebellum contributes to cognitive impairment in hyperammonemic rats.