Effect of ammonium ions on synaptic transmission in the mammalian central nervous system.
It is not surprising that a compound with such unique properties as NH3/NH4+, should have a large variety of biochemical and neurological effects and to find itself implicated in many pathological conditions. Its undissociated (NH3) or dissociated (NH4+) forms, having different physicochemical properties, enter neurons and other cells through differing pathways. These two forms then change internal pH in opposite directions, and initiate a variety of regulatory processes that attempt to overcome these pH changes. In addition, ammonia has a central role in normal intermediary metabolism, and when present in excess, it can disturb reversible reactions in which it participates. The challenge in interpreting these various observations lies in the difficulty in assigning to them a role in the generation of symptoms seen in experimental and clinical hyperammonemias. In this review we have attempted to summarize information available on the effects of ammonium ions on synaptic transmission, a central process in nervous system function. Evidence has been presented to show that ammonium ions, in pathologically relevant concentrations, interfere with glutamatergic excitatory transmission, not by decreasing the release of glutamate, but by preventing its action on post-synaptic AMPA receptors. Furthermore, NH4+ depolarizes neurons to a variable degree, without consistently changing membrane resistance, probably by reducing [K+]i. A decrease in EK+ may also be responsible for decreasing the effectiveness of the outward chloride pump, thus explaining the well known inhibitory effect of NH4+ on the hyperpolarizing IPSP. There is a consensus of opinion that chronic hyperammonemia increases 5HT turnover and this may be responsible for altered sleep patterns seen in hepatic encephalopathy. There does not seem to be a consistent effect on catecholaminergic transmission in hyperammonemias. However, chronic hyperammonemia causes pathological changes in perineuronal astrocytes, which may lead to a reduced uptake of released glutamate and a decreased detoxification of ammonia by the brain. Chronic moderate increase in extracellular glutamate results in a down-regulation of NMDA receptors, while the decreased detoxification of ammonia makes the central nervous system more vulnerable to a sudden hyperammonemia, due, for instance, to an increased dietary intake of proteins or to gastrointestinal bleeding in patients with liver disease. Clearly, data summarized in this review represent only the beginning in the elucidation of the mechanism of ammonia neurotoxicity. It should help, we hope, to direct future investigations towards some of the questions that need to be answered.
Szerb
J C
JC
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
Butterworth
R F
RF
D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000502:physiology; D003128:Coma / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008322:Mammals / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D014364:Tryptophan / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018377:Neurotransmitter Agents; D000644:Quaternary Ammonium Compounds; D017981:Receptors, Neurotransmitter; D018698:Glutamic Acid; D000641:Ammonia; D014364:Tryptophan; D002118:Calcium