Le. Trudeau et al., Activation of neurotransmitter release in hippocampal nerve terminals during recovery from intracellular acidification, J NEUROPHYS, 81(6), 1999, pp. 2627-2635
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.