Mineralocorticoid Receptors Are Indispensable for Nongenomic Modulation of Hippocampal Glutamate Transmission by Corticosterone

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Mineralocorticoid Receptors Are Indispensable for Nongenomic Modulation of Hippocampal Glutamate Transmission by Corticosterone Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone Henk Karst*†, Stefan Berger‡, Marc Turiault§, Francois Tronche§,Gu¨ nther Schu¨ tz‡, and Marian Joe¨ ls* *Swammerdam Institute for Life Sciences, Center for Neurosciences (SILS–CNS), University of Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands; ‡German Cancer Research Institute, 69120 Heidelberg, Germany; and §Centre National de la Recherche Scientifique FRE 2401, College de France, 75231 Paris Cedex, France Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved October 26, 2005 (received for review August 31, 2005) The adrenal hormone corticosterone transcriptionally regulates housed in cages with a light͞dark cycle of 12 h (lights on at 0800 responsive genes in the rodent hippocampus through nuclear hours). Food and water were given ad libitum. The experiments mineralocorticoid and glucocorticoid receptors. Via this genomic were carried out with permission of the local Animal Committee pathway the hormone alters properties of hippocampal cells (file no. DED 91). One mouse per day was decapitated under rest slowly and for a prolonged period. Here we report that cortico- around 0930 hours, i.e., when plasma corticosterone levels are sterone also rapidly and reversibly changes hippocampal signaling. low (ref. 5; Ϸ2 ␮g͞dl). Stress levels of the hormone enhance the frequency of miniature A limited number of experiments was performed in brain- excitatory postsynaptic potentials in CA1 pyramidal neurons and specific GR (12) and MR knockout mice. Details about the reduce paired-pulse facilitation, pointing to a hormone-dependent generation of MR mutants are described in Supporting Text, enhancement of glutamate-release probability. The rapid effect by which is published as supporting information on the PNAS web corticosterone is accomplished through a nongenomic pathway site. In these two mutant lines, immunoreactivity of the GR and involving membrane-located receptors. Unexpectedly, the rapid MR protein, respectively, was lost in all CA1 neurons, which did effect critically depends on the classical mineralocorticoid receptor, express the proteins in control animals. In view of the elevated as evidenced by the effectiveness of agonists, antagonists, and corticosterone levels in GR mutants, both the mutant mice and brain-specific inactivation of the mineralocorticoid but not the their control littermates (GRloxP/loxP) were adrenalectomized, glucocorticoid receptor gene. Rapid actions by corticosterone which in mice resulted in low (Ϸ1 ␮g͞dl) levels of circulating would allow the brain to change its function within minutes after corticosterone, not unlike the levels in adrenally intact mice, stress-induced elevations of corticosteroid levels, in addition to which were decapitated in the morning under rest. responding later through gene-mediated signaling pathways. Slice Preparation and Recording. On the day of the experiment, the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ͉ CA1 animal was decapitated, and the brain was removed from the hippocampus ͉ glucocorticoid receptor knockout ͉ miniature excitatory skull and stored in continuously gassed medium. Transverse postsynaptic current ͉ mineralocorticoid receptor knockout slices of the hippocampus were made with a tissue chopper and stored at room temperature in medium containing 124 mM he release of corticosterone, i.e., the prevailing endogenous NaCl, 3.5 mM KCl, 1.25 mM NaH2PO4, 1.5 mM MgSO4,2mM ϭ Tadrenal corticosteroid in rats and mice, is markedly en- CaCl, 25 mM NaHCO3, and 10 mM glucose (osmolarity 300 hanced after exposure to a stressor. Hormone levels rise within mOsm; pH 7.4). One slice at a time was fully submerged in a minutes and return to baseline Ϸ60–90 min after the stress (1). recording chamber and continuously perfused with the medium Corticosterone can quickly enter the brain and bind to two (32°C, 2–3 ml͞s), as described in ref. 13. Bicuculline methiodide subtypes of discretely localized receptors, the high-affinity min- (20 ␮M, Sigma) was added to block GABAA receptor-mediated eralocorticoid receptor (MR) and the lower-affinity glucocor- signals. ticoid receptor (GR) (2). Hippocampal CA1 neurons abundantly Whole-cell patch clamp recordings were made with an Axo- express both receptor types. Activated corticosteroid receptors patch 200B amplifier (Axon Instruments, Union City, CA) by are known to modify transcription of responsive genes, either using borosilicate glass electrodes (1.5-mm outer diameter; through DNA binding of homodimers or through protein– Hilgenberg, Malsfeld, Germany; pulled on a Sutter micropipette protein interactions with other transcription factors (3, 4). In this puller), with an impedance of 3–4 M⍀. The intracellular pipette way, hippocampal cell properties, like calcium influx, were found solution contained 120 mM Cs methane sulfonate, 17.5 mM to be altered in a slow but persistent manner (5). In recent years, CsCl, 10 mM Hepes, 2 mM MgATP, 0.1 mM NaGTP, 5 mM though, preliminary evidence has accumulated that corticoste- BAPTA, and 10 mM QX-314 (osmolarity ϭ 295 mOsm; pH 7.4), rone can also induce rapid effects in brain (6–10), which would adjusted with CsOH. BAPTA was obtained from Molecular vastly expand the time window over which adrenal hormones can Probes, the sodium channel blocker QX-314 was from Alomone affect brain function. Although in amphibian brain a specific (Jerusalem), and all other chemicals were from Sigma. Under membrane receptor was isolated mediating rapid behavioral visual control the recording electrode was directed toward a CA1 effects (11), the underlying mechanism and presumed mem- neuron by using positive pressure. Once a patch electrode was brane receptor involved in rapid effects of the mammalian sealed on the cell (Ϸ1G⍀) the membrane patch under the hormone remained unresolved. We here demonstrate that a rapid nongenomic effect by corticosterone through membrane- located receptors critically depends on the MR, which hitherto Conflict of interest statement: No conflict declared. was regarded only as a nuclear receptor. This paper was submitted directly (Track II) to the PNAS office. Abbreviations: EPSC, excitatory postsynaptic current; mEPSC, miniature EPSC; MR, miner- Methods alocorticoid receptor; GR, glucocorticoid receptor. Animals. All experiments, unless stated otherwise, were per- †To whom correspondence should be addressed. E-mail: [email protected]. formed on male C57BL͞6 mice, Ϸ6 weeks of age and group- © 2005 by The National Academy of Sciences of the USA 19204–19207 ͉ PNAS ͉ December 27, 2005 ͉ vol. 102 ͉ no. 52 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0507572102 Downloaded by guest on September 23, 2021 Fig. 1. Corticosterone rapidly and reversibly enhances mEPSC frequency in hippocampal cells. (A) Typical example showing enhanced mEPSC frequency in a CA1 pyramidal cell during 100 nM corticosterone (cort) application (Middle) compared with the control situation (Top). Bottom shows the typical shape of an mEPSC. (B) Example showing that mEPSC frequency is rapidly and reversibly enhanced by corticosterone but not by vehicle (0.009% ethanol). (C) Cumulative frequency histogram of the mEPSC frequency in a CA1 hippocampal cell, showing that the mEPSC frequency is enhanced in the presence of corticosterone and returns to pretreatment levels after corticosterone has been washed out. (D) Percentual increase in mEPSC frequency caused by various concentrations of corticosterone (filled circles, based on n ϭ 3–5 cells for each concentration), showing that 10 nM corticosterone, but not lower concentrations of corticosterone, induces a significant (P Ͻ 0.05) increase in mEPSC frequency. The membrane-impermeable BSA–corticosterone conjugate (100 nM; n ϭ 5) also resulted in a marked increase in mEPSC frequency. In the presence of the protein synthesis inhibitor cycloheximide (100 nM; n ϭ 5), corticosterone was still able to enhance the mEPSC frequency. Symbols represent the mean ϩ SEM values. electrode was ruptured and the cell was held at a holding receptor blocker CNQX or the selective ␣-amino-3-hydroxy-5- potential of Ϫ70 mV. Recordings with an uncompensated series methyl-4-isoxazolepropionic acid (AMPA) receptor blocker resistance of Ͻ2.5 times the pipette resistance were accepted for GYKI 53655 was perfused to confirm that the mEPSCs were analysis. Data acquisition was performed with PCLAMP 8.2 and indeed mediated by AMPA receptors. The digitized data (stored analyzed with CLAMPFIT 8.2 and STRATHCLYDE software (J. on PC via Digidata interface) were analyzed off-line by using Dempster, University of Strathclyde, Glasgow, U.K.). STRATHCLYDE software with detection threshold levels set above 5 pA. The currents were identified as mEPSCs when the rise time Stimulus Evoked of Excitatory Postsynaptic Currents (EPSCs). A bi- was faster than the decay time (13). Of all cells measured, the polar stainless steel stimulus electrode was placed in the Schaffer following mEPSC characteristics were determined: inter- collaterals. Biphasic stimuli were applied through a stimulus mEPSC interval and frequency, rise time, peak amplitude, and isolator driven by PCLAMP 8.2. Input–output curves of EPSCs ␶ of decay. The decay of each mEPSC was fitted with a evoked in CA1 neurons were made at holding potential (Ϫ70 monoexponential curve using the WHOLECELL program of the mV) by stimuli of increasing intensities (from 16 ␮A to 500 ␮A), STRATHCLYDE software.
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