Differential effects of chronic hyperammonemia on modulation of the glutamate–nitric oxide–cGMP pathway by metabotropic glutamate receptor 5 and low and high affinity AMPA receptors in cerebellum in vivo

Previous studies show that chronic hyperammonemia impairs learning ability of rats by impairing the glutamate–nitric oxide (NO)–cyclic guanosine mono-phosphate (cGMP) pathway in cerebellum. Three types of glutamate receptors cooperate in modulating the NO–cGMP pathway: metabotropic glutamate receptor 5 (mGluR5), (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors. The aim of this work was to assess whether hyperammonemia alters the modulation of this pathway by mGluR5 and AMPA receptors in cerebellum in vivo. The results support that in control rats: (1) low AMPA concentrations (0.1 mM) activate nearly completely Ca2+-permeable (glutamate receptor subunit 2 (GluR2)-lacking) AMPA receptors and the NO–cGMP pathway; (2) higher AMPA concentrations (0.3 mM) also activate Ca2+-impermeable (GluR2-containing) AMPA receptors, leading to activation of NMDA receptors and of NO–cGMP pathway. Moreover, the data support that chronic hyperammonemia: (1) reduces glutamate release and activation of the glutamate–NO–cGMP pathway by activation of mGluR5; (2) strongly reduces the direct activation by AMPA receptors of the NO–cGMP pathway, likely due to reduced entry of Ca2+ through GluR2-lacking, high affinity AMPA receptors; (3) strongly increases the indirect activation of the NO–cGMP pathway by high affinity AMPA receptors, likely due to increased entry of Na+ through GluR2-lacking AMPA receptors and NMDA receptors activation; (4) reduces the indirect activation of the NO–cGMP pathway by low affinity AMPA receptors, likely due to reduced activation of NMDA receptors.

► Chronic moderate hyperammonemia reduces mGluR5-induced increase in extracellular glutamate in cerebellum in vivo.
► Chronic moderate hyperammonemia reduces activation of the glutamate–NO–cGMP pathway by mGluR5 in cerebellum in vivo.
► Chronic moderate hyperammonemia reduces activation of the glutamate–NO–cGMP pathway by low affinity AMPA receptors.
► Chronic moderate hyperammonemia enhances activation of glutamate–NO–cGMP pathway by high affinity AMPA receptors.