Chronic exposure to ammonia alters pathways modulating phosphorylation of microtubule-associated protein 2 in cerebellar neurons in culture

Hyperammonemia is considered the main cause for the neurological alteration s found in hepatic failure. However, the mechanisms by which high ammonia l evels impair cerebral function are not well understood. It has been shown t hat chronic hyperammonemia impairs signal transduction pathways associated with NMDA receptors and also alters phosphorylation of some neuronal protei ns. The aim of the present work was to analyze the effects of chronic expos ure to ammonia on phosphorylation of microtubule-associated protein 2 (MAP- 2) in intact neurons in culture and to assess whether modulation of MAP-2 p hosphorylation by glutamate receptor-associated transduction pathways is al tered in neurons chronically exposed to ammonia. It is shown that chronic e xposure to ammonia increases basal phosphorylation of MAP-2 by similar to 7 0%. This effect seems to be due to a decreased tonic activation of NMDA rec eptors and of calcineurin. Chronic exposure to ammonia also alters the modu lation of MAP-2 phosphorylation by NMDA receptors and metabotropic glutamat e receptors. In neurons exposed to ammonia, treatment with NMDA for 30 min induced a significant decrease in phosphorylation of MAP-2. Activation of m etabotropic glutamate receptors with (1S,3R)-1 -aminocyclopentane-1,3-dicar boxylic acid significantly increased phosphorylation of MAP in control neur ons, whereas in neurons exposed to ammonia the response was the opposite, w ith 1-aminocyclopentane-1,3-dicarboxylic acid inducing a dephosphorylation of MAP-2. These results indicate that ammonia alters significantly signal t ransduction pathways associated with different types of glutamate receptors . This would lead therefore to significant alterations in glutamatergic neu rotransmission, which would contribute to the neurological alterations foun d in hyperammonemia and in hepatic encephalopathy.