Fast changes of NMDA and AMPA receptor activity under acute hyperammonemia in vitro

It was established in experiments on cell cultures of neurons and astrocytes that ammonium ions at concentrations of 4-8 mM cause hyperexcitation of the neuronal network, as a result of which there is a disturbance of calcium homeostasis, which can lead to the death of neurons. In the present study, we investigated the effect of toxic doses of ammonium (8 mM NH₄Cl) on the activity of NMDA and AMPA receptors and the role of these receptors in spontaneous synchronous activity (SSA). In a control experiment in the absence of NH₄Cl, SSA is not suppressed by NMDA receptor inhibitors, but is suppressed by AMPA receptor antagonists. In the presence of toxic doses of NH₄Cl, SSA is completely inhibited by NMDA receptor inhibitors in 63% of neurons and by AMPA receptor inhibitors in 33% of neurons. After short-term applications of toxic doses of ammonium, the amplitude of the Ca²⁺ response to 10 μM NMDA increases, and decreases in response to 500 nM FW (agonist of AMPA receptors). NMDA receptor blocker MK-801 (20 μM), competitive antagonist D-AP5 (10 μM) and competitive AMPA receptor antagonist NBQX (2 μM) abolished the activating ammonium mediated effect on the NMDA receptors while only MK-801, but not NBQX, abolished the inhibiting ammonium mediated effect on AMPA receptors. These data indicate that under acute hyperammonemia, the activity of NMDA receptors increases, while the activity of AMPA receptors decreases. This phenomenon could explain such a wide range of toxic effects of ammonium ions mediated by NMDA receptors.