Activation of neurotransmitter release in hippocampal nerve terminals during recovery from intracellular acidification

Activation of neurotransmitter release in hippocampal nerve terminals durin g recovery from intracellular acidification. J. Neurophysiol. 81. 2627-2635 , 1999. Intracellular pH may be an important variable regulating neurotrans mitter release. A number of pathological conditions, such as anoxia and isc hemia, are known to influence intracellular pH, causing acidification of br ain cells and excitotoxicity. We examined the effect of acidification on qu antal glutamate release. Although acidification caused only modest changes in release, recovery from acidification was associated with a Very large (6 0-fold) increase in the frequency of miniature excitatory postsynaptic curr ents (mEPSCs) in cultured hippocampal neurons. This was accompanied by a bl ock of evoked EPSCs and a rise in intracellular free Ca2+ ([Ca2+](i)). The rise in mEPSC frequency required extracellular Ca2+ but influx did not occu r through voltage-operated channels. Because acidic pH is known to activate the Na+/H+ antiporter, we hypothesized that a resulting Na+ load could dri ve Ca2+ influx through the Na+/Ca2+ exchanger during recovery from acidific ation. This hypothesis is supported by three observations. First, intracell ular Na+ rises during acidification. Second, the elevation in [Ca2+](i) and mEPSC frequency during recovery from acidification is prevented by the Na/H+ antiporter blocker EIPA applied during the acidification step. Third, t he rise in free Ca2+ and mEPSC frequency is blocked by the Na+/Ca2+ exchang er:er blocker dimethylbenzamil. We thus propose that during recovery from;o m intracellular acidification a massive activation of neurotransmitter rele ase occurs because the successive activation of the Na+/H+ and Na+/Ca2+ exc hangers in nerve terminals leads to an elevation of intracellular calcium. Our results suggest that changes in intracellular pH and especially recover y from acidification have extensive consequences for the release process in nerve terminals. Excessive release of,of glutamate through the proposed me chanism could be implicated in excitotoxic insults after anoxic or ischemic episodes.