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Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

Molecular Psychiatry volume 10, pages 790–798 (2005)Cite this article

Abstract

An important question arising from previous observations in vivo is whether glucocorticoids can directly influence neuronal survival in the hippocampus. To this end, a primary postnatal hippocampal culture system containing mature neurons and expressing both glucocorticoid (GR) and mineralocorticoid (MR) receptors was developed. Results show that the GR agonist dexamethasone (DEX) targets neurons (microtubule-associated protein 2-positive cells) for death through apoptosis. GR-mediated cell death was counteracted by the MR agonist aldosterone (ALDO). Antagonism of MR with spironolactone ([7α-(acetylthio)-3-oxo-17α-pregn-4-ene-21 carbolactone] (SPIRO)) causes a dose-dependent increase in neuronal apoptosis in the absence of DEX, indicating that nanomolar levels of corticosterone present in the culture medium, which are sufficient to activate MR, can mask the apoptotic response to DEX. Indeed, both SPIRO and another MR antagonist, oxprenoate potassium ((7α,17α)-17-hydroxy-3-oxo-7-propylpregn-4-ene-21-carboxylic acid, potassium salt (RU28318)), accentuated DEX-induced apoptosis. These results demonstrate that GRs can act directly to induce hippocampal neuronal death and that demonstration of their full apoptotic potency depends on abolition of survival-promoting actions mediated by MR.

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Acknowledgements

We thank Rosa Buric, Julia Deicke and Dieter Fischer for technical assistance. CC, JL, and YW were supported by fellowships from the Max Planck Society. The work was partly supported by the German Academic Exchange Service/Magyar Ösztöndij Bizottság (DAAD 323-PPP Ungarn), Acções Integradas Luso-Alemãs (DAAD-CRUP-ICCTI 314/Al-p-dr) and the European Commission (QLG3-CT-2000-00844).

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  1. C Crochemore, J Lu and Y Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Munich, Germany

    C Crochemore, J Lu, Y Wu, F Holsboer & O F X Almeida

  2. Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary

    Z Liposits

  3. Life and Health Science Research Institute, University of Minho School of Health Sciences, Braga, Portugal

    N Sousa

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  1. C Crochemore
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Correspondence to O F X Almeida.

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Crochemore, C., Lu, J., Wu, Y. et al. Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation. Mol Psychiatry 10, 790–798 (2005). https://doi.org/10.1038/sj.mp.4001679

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