Hypoxia-induced depression of synaptic transmission becomes irreversible by intracellular accumulation of non-excitatory amino acids

The intracellular accumulation of some amino acids (AAs), mainly glutamine, can contribute to brain edema observed during liver failure. We recently demonstrated that individual applications of high concentrations (10 mM) of some non-excitatory AAs increase the electrical resistance of hippocampal slices, indicating cell swelling. Therefore, we pondered whether an AA mixture's application might cause cell swelling at a physiological concentration range. In rat hippocampal slices, we carried out extra- and intracellular electrophysiological recordings and AAs analysis to address this question. We applied a mixture of 19 AAs at their plasmatic concentrations (Plasma solution: Ala, Gly, Gln, His, Ser, Tau, Thr, Arg, Leu, Met, Pro, Val, Asn, Cys, Phe, Ile, Lys, Tyr, and Trp). This solution was afterward divided into two according to the individual AAs at 10 mM concentration inducing synaptic potentiation (Plasma1, containing the first seven AAs of Plasma) or not (Plasma2, with the remaining AAs). Plasma application increased evoked field potentials requiring extracellular chloride. This effect was mimicked by the Plasma1 but not the Plasma2 solution. Plasma1-induced potentiation was independent of changes in release probability, basic electrophysiological membrane properties, and NMDAR activation. AAs in Plasma1 act cooperatively to accumulate intracellularly and to induce synaptic potentiation. In the presence of Plasma1, the reversible synaptic depression caused by a 40-min hypoxia period turned into an irreversible disappearance of synaptic potentials through an NMDAR-dependent mechanism. The presence of a system A transport inhibitor did not block Plasma1-mediated effects. These results indicate that cell swelling, induced by the accumulation of non-excitotoxic AAs through unidentified transporters, might foster deleterious effects produced by hypoxia-ischemia episodes.

Automated summary

The study demonstrates that the application of an amino acid mixture at physiological concentrations can lead to cell swelling and affect synaptic function. Specifically, the amino acids in Plasma1 accumulate intracellularly and induce synaptic potentiation.