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Combinatorial actions of glucocorticoid and mineralocorticoid stress hormone receptors are required for preventing neurodegeneration of the mouse hippocampus

TitoloCombinatorial actions of glucocorticoid and mineralocorticoid stress hormone receptors are required for preventing neurodegeneration of the mouse hippocampus
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2021
AutoriOakley, Robert H., Whirledge Shannon D., Petrillo Maria Grazia, Riddick Natallia V., Xu Xiaojiang, Moy Sheryl S., and Cidlowski John A.
RivistaNeurobiology of Stress
Volume15
Type of ArticleArticle
ISSN23522895
Abstract

Chronic stress contributes to numerous human pathologies including cognition impairments and psychiatric disorders. Glucocorticoids are primary stress hormones that activate two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR), that are both highly expressed in the hippocampus. To investigate potential combinatorial actions of hippocampal GR and MR, we developed mice with conditional knockout of both GR and MR in the hippocampus and compared them to their single knockout counterparts. Mice lacking MR alone or both GR and MR in the hippocampus exhibited altered expression of multiple CA2-specific neuronal markers and enhanced cue-dependent learning in a conditioned fear test. Provocatively, in contrast to the single knockouts, mice depleted of both GR and MR showed profound neurodegeneration of the hippocampus. Neuronal death was increased and neurogenesis was reduced in the dentate gyrus of the double knockout mice. Global gene expression assays of the knockout mice revealed a synergistic increase in the number of dysregulated genes in the hippocampus lacking both GR and MR. This large cohort of genes reliant on both GR and MR for expression was strongly associated with cell death and cell proliferation pathways. GR/MR complexes were detected in CA1 and dentate gyrus neurons suggesting receptor heterodimers contribute to the joint actions of GR and MR. These findings reveal an obligate role for MR signaling in regulating the molecular phenotype of CA2 neurons and demonstrate that combinatorial actions of GR and MR are essential for preserving dentate gyrus neurons and maintaining hippocampal health. © 2021

Note

Cited by: 12; All Open Access, Gold Open Access, Green Open Access

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85111003335&doi=10.1016%2fj.ynstr.2021.100369&partnerID=40&md5=398f35e26767fe1320ec2e9ebb152c2b
DOI10.1016/j.ynstr.2021.100369
Citation KeyOakley2021