Pharmacological and genetic accumulation of hypoxia-inducible factor-1α enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth factor

Yu Fei Huang, Chih Hao Yang, Chiung Chun Huang, Ming Hong Tai, Kuei Sen Hsu

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Hypoxia-inducible factor-1 (HIF-1) is an important transcriptional factor in mammalian cells for coordination of adaptive responses to hypoxia. It consists of a regulatory subunit HIF-1α, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1β. In addition to the well characterized oxygen-dependent mode of action of HIF-1, recent work has shown that various growth factors and cytokines stimulate HIF-1α expression, thereby triggering transcription of numerous hypoxia-inducible genes by oxygen-independent mechanisms. In this study, we examined whether accumulation of HIF-1α induced by insulin-like growth factor-1 (IGF-1) has a regulatory role in excitatory synaptic transmission in hippocampal neuron cultures. Our results show that IGF-1 induced a time- and dose-dependent increase in HIF-1α expression that was blocked by pretreatment with selective IGF-1 receptor antagonist, transcriptional inhibitor, and translational inhibitors. In addition, pharmacological blockade of the phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin signaling pathway, but not extracellular signal-regulated kinase, inhibited IGF-1-induced HIF-1α expression. More importantly, the increase in HIF-1α expression induced by IGF-1 was accompanied by increasing levels of vascular endothelial growth factor (VEGF) mRNA and protein, which enhanced excitatory synaptic transmission. In parallel, blockade of HIF-1α activity by echinomycin or lentiviral infection with dominant-negative mutant HIF-1α or short hairpin RNA targeting HIF-1α inhibited the increase in expression of VEGF and the enhancement of synaptic transmission induced by IGF-1. Conversely, transfection of constitutively active HIF-1α into neurons mimicked the effects of IGF-1 treatment. Together, these results suggest that HIF-1α accumulation can enhance excitatory synaptic transmission in hippocampal neurons by regulating production of VEGF.

Original languageEnglish
Pages (from-to)6080-6093
Number of pages14
JournalJournal of Neuroscience
Volume30
Issue number17
DOIs
Publication statusPublished - Apr 28 2010
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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