☆ 4.3 Article

HIF-1α-mediated upregulation of SERCA2b: The endogenous mechanism for alleviating the ischemia-induced intracellular Ca2+ store dysfunction in CA1 and CA3 hippocampal neurons

CELL CALCIUM (2016)

Journal

CELL CALCIUM

Volume 59, Issue 5, Pages 251-261

Publisher

ELSEVIER SCI LTD

DOI: 10.1016/j.ceca.2016.02.014

Keywords

Prolonged ischemic conditions; Intracellular free Ca2+ concentration; ([Ca2+](i)); HIF-1 alpha; Ca2+-ATPase; SERCA2b; CA1 and CA3 hippocampal neurons

Funding

NASU Biotechnology
Functional Genomics
DFFD [F47/066]
NASU Nanotechnology
Functional Genomics and Metabolomics grants
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Abstract

Pyramidal neurons of the hippocampus possess differential susceptibility to the ischemia-induced damage with the highest vulnerability of CA1 and the lower sensitivity of CA3 neurons. This damage is triggered by Ca2+-dependent excitotoxicity and can result in a delayed cell death that might be potentially suspended through activation of endogenous neuroprotection with the hypoxia-inducible transcription factors (HIF). However, the molecular mechanisms of this neuroprotection remain poorly understood. Here we show that prolonged (30 min) oxygen and glucose deprivation (OGD) in situ impairs intracellular Ca2+ regulation in CA1 rather than in CA3 neurons with the differently altered expression of genes coding Ca2+-ATPases: the mRNA level of plasmalemmal Ca2+-ATPases (PMCA1 and PMCA2 subtypes) was downregulated in CA1 neurons, whereas the mRNA level of the endoplasmic reticulum Ca2+-ATPases (SERCA2b subtype) was increased in CA3 neurons at 4 h of re-oxygenation after prolonged OGD. These demonstrate distinct susceptibility of CAI and CA3 neurons to the ischemic impairments in intracellular Ca2+ regulation and Ca2+-ATPase expression. Stabilization of HIF-1 alpha by inhibiting HIF-1 alpha hydroxylation prevented the ischemic decrease in both PMCA1 and PMCA2 mRNAs in CA1 neurons, upregulated the SERCA2b mRNA level and eliminated the OGD-induced Ca2+ store dysfunction in these neurons. Cumulatively, these findings reveal the previously unknown HIF-la-driven upregulation of Ca2+-ATPases as a mechanism opposing the ischemic impairments in intracellular Ca2+ regulation in hippocampal neurons. The ability of HIF-1 alpha to modulate expression of genes coding Ca2+-ATPases suggests SERCA2b as a novel target for HIF-1 and may provide potential implications for HIF-1 alpha-stabilizing strategy in activating endogenous neuroprotection. (C) 2016 Elsevier Ltd. All rights reserved.

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Optogenetics reveals paradoxical network stabilizations in hippocampal CA1 and CA3

Laurel Watkins de Jong, Mohammadreza Mohagheghi Nejad, Euisik Yoon, Sen Cheng, Kamran Diba

Summary: Recurrent connectivity and feedback inhibition from inhibitory neurons play crucial roles in determining the dynamics and computational properties of neuronal circuits. Through optogenetic manipulations and large-scale unit recordings, paradoxical responses were observed in both CA1 and CA3 regions of the hippocampus, where subsets of cells increased firing during photoinhibition while others decreased firing during photoexcitation. These paradoxical responses were more prominent in CA3 and simulations confirmed that both CA1 and CA3 hippocampal regions exhibit inhibition-stabilized networks with strong recurrent excitation.

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