Membrane Mineralocorticoid but not Glucocorticoid Receptors of the Dorsal Hippocampus Mediate the Rapid Effects of Corticosterone on Memory Retrieval

Abstract

This study was aimed at determining the type of the glucocorticoid membrane receptors (mineralocorticoid receptors (MRs) or glucocorticoid receptors (GRs)) in the dorsal hippocampus (dHPC) involved in the rapid effects of corticosterone or stress on memory retrieval. For that purpose, we synthesized corticosterone–3-O-carboxymethyloxime–bovine serum albumin conjugate (Cort–3CMO–BSA) conjugate (a high MW complex that cannot cross the cell membrane) totally devoid of free corticosterone, stable in physiological conditions. In a first experiment, we evidenced that an acute stress (electric footshocks) induced both a dHPC corticosterone rise measured by microdialysis and memory retrieval impairment on delayed alternation task. Both the endocrinal and cognitive effects of stress were blocked by metyrapone (a corticosterone synthesis inhibitor). In a second experiment, we showed that bilateral injections of either corticosterone or Cort–3CMO–BSA in dHPC 15 min before memory testing produced impairments similar to those resulting from acute stress. Furthermore, we showed that anisomycin (a protein synthesis inhibitor) failed to block the deleterious effect of Cort–3CMO–BSA on memory. In a third experiment, we evidenced that intra-hippocampal injection of RU-28318 (MR antagonist) but not of RU-38486 (GR antagonist) totally blocked the Cort–3CMO–BSA-induced memory retrieval deficit. In a fourth experiment, we demonstrated that RU-28318 administered 15 min before stress blocked the stress-induced memory impairments when behavioral testing occurred 15 min but not 60 min after stress. Overall, this study provides strong in vivo evidence that the dHPC membrane GRs, mediating the rapid and non-genomic effects of acute stress on memory retrieval, are of MR but not GR type.

Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders

“…Further, 50 mg spironolactone versus placebo for 6 weeks in obese individuals improved a hippocampal-dependant task-associate learning, which involves remembering that two previously unrelated items are associated with each other [56]. This result is consistent with preclinical studies suggesting that the hippocampal MR has a role in hippocampal memory modulation [57].…”

Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

“…Although the latter was found to be sensitive to G i/o inhibition (PTX) and to a general inhibitor of GPCR function (SCH20267), the nature of the putative membrane-localized CORT receptor remains unknown. Although some earlier studies observed immunoreactivity corresponding to the classical, nuclear GR in the plasma membrane (12,15,40,42), more recent ones have proposed that the fast actions of CORT in hippocampal neurons are mediated by translocated nuclear MR (7,43). It is pertinent to note that recent work has implicated an orphan GPCR in fast signaling by two other steroid hormones, estradiol and aldosterone (44,45); the latter is enzymatically (18-hydroxylase and 18-hydroxysteroid dehydrogenase) derived from CORT.…”

Stress-Induced Memory Retrieval Impairments: Different Time-Course Involvement of Corticosterone and Glucocorticoid Receptors in Dorsal and Ventral Hippocampus

“…Indeed, in vivo microdialysis is an extremely powerful method to study the highly dynamic neurotransmitter responses in the field of stress physiology and behavior (Linthorst and Reul, 2008; Dorey et al , 2011). …”

“…The doses of antagonists were selected according to a previous study (Dorey et al , 2011). The antagonists were bilaterally injected 15 min before stress and 30 min before the test session.…”