The Journal of Neurophysiology Vol. 81 No. 6 June 1999, pp. 2627-2635
Copyright ©1999 by the American Physiological Society

Activation of Neurotransmitter Release in Hippocampal Nerve Terminals During Recovery From Intracellular Acidification

 ¹Departments of Pharmacology and Psychiatry, Faculty of Medicine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada; and  ²Laboratory of Cellular Signaling, Department of Zoology and Genetics, Iowa State University, Ames, Iowa 50010

Trudeau, Louis-Eric, Vladimir Parpura, and Philip G. Haydon. Activation of Neurotransmitter Release in Hippocampal Nerve Terminals During Recovery From Intracellular Acidification. J. Neurophysiol. 81: 2627-2635, 1999.Activation of neurotransmitter release in hippocampal nerve terminals during recovery from intracellular acidification. Intracellular pH may be an important variable regulating neurotransmitter release. A number of pathological conditions, such as anoxia and ischemia, are known to influence intracellular pH, causing acidification of brain cells and excitotoxicity. We examined the effect of acidification on quantal glutamate release. Although acidification caused only modest changes in release, recovery from acidification was associated with a very large (60-fold) increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons. This was accompanied by a block of evoked EPSCs and a rise in intracellular free Ca²⁺ ([Ca²⁺]_i). The rise in mEPSC frequency required extracellular Ca²⁺, but influx did not occur through voltage-operated channels. Because acidic pH is known to activate the Na⁺/H⁺ antiporter, we hypothesized that a resulting Na⁺ load could drive Ca²⁺ influx through the Na⁺/Ca²⁺ exchanger during recovery from acidification. This hypothesis is supported by three observations. First, intracellular 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, the rise in free Ca²⁺ and mEPSC frequency is blocked by the Na⁺/Ca²⁺ exchanger blocker dimethylbenzamil. We thus propose that during recovery from intracellular acidification a massive activation of neurotransmitter release occurs because the successive activation of the Na⁺/H⁺ and Na⁺/Ca²⁺ exchangers in nerve terminals leads to an elevation of intracellular calcium. Our results suggest that changes in intracellular pH and especially recovery from acidification have extensive consequences for the release process in nerve terminals. Excessive release of glutamate through the proposed mechanism could be implicated in excitotoxic insults after anoxic or ischemic episodes.