Presynaptic silencing is an endogenous neuroprotectant during excitotoxic insults

Joshua Hogins, Devon C. Crawford, Xiaoping Jiang, Steven Mennerick

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Glutamate release is a root cause of acute and delayed neuronal damage in response to hypoxic/ischemic insults. Nevertheless, therapeutics that target the postsynaptic compartment have been disappointing clinically. Here we explored whether presynaptic silencing (muting) of glutamatergic terminals is sufficient to reduce excitotoxic damage resulting from hypoxia and oxygen/glucose deprivation. Our evidence suggests that strong depolarization, previously shown to mute glutamate synapses, protects neurons by a presynaptic mechanism that is sensitive to inhibition of the proteasome. Postsynaptic Ca2+ rises in response to glutamate application and toxicity in response to exogenous glutamate treatment were unaffected by depolarization preconditioning. These features strongly suggest that reduced glutamate release explains preconditioning protection. We addressed whether hypoxic depolarization itself induces presynaptic silencing, thereby participating in the damage threshold for hypoxic insult. Indeed, we found that the hypoxic insult increased the percentage of mute glutamate synapses in a proteasome-dependent manner. Furthermore, proteasome inhibition exacerbated neuronal loss to mild hypoxia and prevented hypoxia-induced muting. In total our results suggest that presynaptic silencing is an endogenous neuroprotective mechanism that could be exploited to reduce damage from insults involving excess synaptic glutamate release.

Original languageEnglish
Pages (from-to)516-525
Number of pages10
JournalNeurobiology of Disease
Volume43
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • Excitotoxicity
  • Glutamate
  • Hippocampus
  • Homeostasis
  • Ischemia
  • Synaptic plasticity

Fingerprint

Dive into the research topics of 'Presynaptic silencing is an endogenous neuroprotectant during excitotoxic insults'. Together they form a unique fingerprint.

Cite this