Chronic exposure to ammonia alters the modulation of phosphorylation of microtubule-associated protein 2 by metabotropic glutamate receptors 1 and 5 in cerebellar neurons in culture

Hyperammonemia impairs signal transduction associated to glutamate receptors and phosphorylation of some neuronal proteins including microtubule-associated protein 2 (MAP-2). The aim of this work was to analyze the effects of hyperammonemia on modulation of MAP-2 phosphorylation by metabotropic glutamate receptors (mGluRs) in rat cerebellar neurons in culture. Hyperammonemia increased basal phosphorylation of MAP-2 (180%). Activation of mGluRs 1 and 5 with (S)-3,5-dihydroxyphenylglycine (DHPG) increased MAP-2 phosphorylation (170%) in control neurons but not in neurons exposed to ammonia. Activation of mGluRs 2 and 3 with (2S,3S,4S)-CCG/(2S, 1′S,2′S)-2-(carboxycyclopropyl)glycine increased slightly (25%) MAP-2 phosphorylation in neurons exposed to ammonia or not. Activation of mGluR5 with (±)-trans-azetidine-2,4-dicarboxylic acid increased MAP-2 phosphorylation (24%) in control neurons but decreased it by 56% in neurons exposed to ammonia. Activation of mGluR1 using 2-methyl-6-(phenylethynyl)pyridine and DHPG increased MAP-2 phosphorylation 183% in control neurons but only 89% in neurons exposed to ammonia. In control neurons mGluR1 activation greatly increases phosphorylation of MAP-2, while activation of mGluRs 5, 2 or 3 increased it slightly. Taken together, hyperammonemia reduces the increase in MAP-2 phosphorylation induced by mGluR1activation. Moreover, in neurons exposed to ammonia activation of mGluR5 reduces MAP-2 phosphorylation. These effects reflect significant alterations in signal transduction associated to mGluR1 and mGluR5 in hyperammonemia that may contribute to altered glutamatergic neurotransmission and to the neurological alterations in hyperammonemia and hepatic encephalopathy.