Mechanisms underlying presynaptic Ca2+ transient and vesicular glutamate release at a CNS nerve terminal during in vitro ischaemia

Seul Yi Lee, Jun Hee Kim

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Key points: Here we demonstrate presynaptic responses and mechanisms of increased vesicular glutamate release during in vitro ischaemia in the calyx of Held terminal, an experimentally accessible presynaptic terminal in the CNS. The ischaemia-induced increase in presynaptic Ca2+ was mediated by both Ca2+ influx and Ca2+-induced Ca2+ release from intracellular stores. The reverse operation of the plasma membrane Na+/Ca2+ exchanger (NCX) plays a key role in Ca2+ influx for triggering Ca2+ release from intracellular stores at presynaptic terminals during in vitro ischaemia. Ca2+ uptake via NCX underlies the ischaemia-induced Ca2+ rise and the consequent increase in vesicular glutamate release from presynaptic terminals in the early phase of brain ischaemia. An early consequence of brain ischaemia is an increase in vesicular glutamate release from presynaptic terminals. However, the mechanisms of this increased glutamate release are not fully understood. Here we studied presynaptic responses and mechanisms of increased glutamate release during in vitro ischaemia, using pre- and postsynaptic whole-cell recordings and presynaptic Ca2+ imaging at the calyx of Held synapse in rat brainstem slices. Consistent with results from other brain regions, in vitro ischaemia significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without affecting their amplitude, suggesting that ischaemia enhances vesicular glutamate release from presynaptic terminals. We found that ischaemia-induced vesicular glutamate release was dependent on a rise in basal Ca2+ at presynaptic terminals, which resulted from extracellular Ca2+ influx and Ca2+ release from intracellular stores. During early ischaemia, increased Ca2+ influx into presynaptic terminals was due to reverse operation of the plasma membrane Na+/Ca2+ exchanger (NCX) rather than presynaptic depolarization or voltage-activated Ca2+ currents. KB-R7943, an inhibitor of NCX, prevented the ischaemia-induced increases in presynaptic Ca2+ and vesicular glutamate release. In addition, the removal of extracellular Na+ completely inhibited the ischaemia-induced Ca2+ rise. It therefore appears that a link between Na+ accumulation and Ca2+ uptake via NCX underlies the ischaemia-induced Ca2+ rise and the consequent increase in vesicular glutamate release from presynaptic terminals in the early phase of brain ischaemia.

Original languageEnglish (US)
Pages (from-to)2793-2806
Number of pages14
JournalJournal of Physiology
Volume593
Issue number13
DOIs
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Physiology

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