Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices

BRAIN

RESEARCH ELSEVIER

Brain Research 738 (1996) 229-235

Research report

Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices Constantine Pavlides *, Sonoko Ogawa, Akihisa Kimura, Bruce S. McEwen Box 298, The Rockefeller University, 1230 York Avenue, New York, N Y 10021, USA

Accepted 18 June 1996

Abstract

We previously demonstrated in the dentate gyrus (DG) of anesthetized and freely behaving rats that both acute as well as chronic administration of corticosterone produces a suppression in long-term potentiation (LTP). In subsequent studies we showed, again in the DG, that activation of the two types of adrenal steroid receptors (mineralocorticoid (MR) and glucocorticoid (GR)) produce biphasic effects on synaptic plasticity; activation of MR produces an enhancement while activation of GR produces a suppression in LTP. In a separate study, we further demonstrated in rats administered the specific GR agonist RU 28362 that high-frequency stimulation, which normally produces LTP, instead produced long-term depression (LTD) in these animals. In the present study we investigated the effects of MR and GR activation by adrenal steroids on synaptic plasticity of the hippocampal CA1 field, but we studied this ex vivo, in a slice preparation. The results indicate that, as in our studies in the DG, adrenal steroids produce biphasic effects: in ADX rats, aldosterone (a specific MR agonist) enhanced while RU 28362 suppressed synaptic plasticity. Unlike the in vivo preparation, however, rarely was LTD observed in the animals receiving RU 28362. Also, ADX itself did not produce noticeable effects on synaptic plasticity. The present results are in agreement with previous studies showing that elevations in corticosterone or an acute episode of experimentally induced stress in vivo causes a suppression in LTP in the hippocampal CA1 field, in vitro. Keywords: Mineralocorticoid receptor; Glucocorticoid receptor; Aldosterone; Corticosterone; Synaptic plasticity; Long-term potentiation; CA1

1. I n t r o d u c t i o n

Previous studies from our laboratory demonstrated that adrenal steroids can modulate synaptic plasticity in the dentate gyrus (DG) of the hippocampus. More specifically, we showed in intact (non-ADX), anesthetized rats that both acute as well as chronic administration of corticosterone suppress long-term potentiation (LTP) [26]. In later studies, we showed, again in the D G o f anesthetized rats, that the two types of adrenal steroid receptors - mineralocorticoid (MR) and glucocorticoid (GR) - produce opposing effects on LTP, with M R activation producing an enhancement and G R activation producing a suppression [25] in LTP. These findings were extended to freely behaving animals [22]. It was further demonstrated in these

Abbreviations: Aldo, aldosterone; ADX, adrenalectomy; BL, baseline; HFS, high-frequency stimulation; LTD, long-term depression; LTP, hmg-term potentiation; MF, mossy fibers; Sch, Schaffer collaterals * Corresponding author. Fax: (1) (212) 327-8343; e-mail: [email protected]

studies that M R activation not only enhances but also prolongs the maintenance of LTP (48 h or longer) following the initial induction. In contrast, not only did GR activation suppress LTP but at higher levels of corticosterone or RU 28362 produced a long-term depression (LTD) in synaptic transmission - with high frequency stimulation which normally produces LTP. A number of studies have previously reported that an episode of acute stress in vivo produces a suppression in LTP in the CA1 field of hippocampal slices [8-10,30,31]. In these experiments, the suppression of LTP by stress was negatively correlated with plasma corticosterone levels. A more recent study, however, has reported that the relationship between plasma corticosterone levels and prime burst potentiation (PBP; a variant of LTP) more closely resembles an inverted-U function: low and high levels of plasma corticosterone produce a suppression while intermediate levels of corticosterone are required for m a x i m u m plasticity [7]. All of the above mentioned studies were performed in the CA1 field - the majority of these were done in hippocampal slices.

0006-8993/96/$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved. Pll S0006- 8993 (96)00776-7

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GR are distributed throughout the brain; however, their highest concentration is in the hippocampus while MR are mainly found in the hippocampus. Within this structure, both MR and GR are highly localized in the DG and CA1 and CA3 fields [11-13,36]. Although this is the case, it is becoming evident that the various subfields show different susceptibilities to adrenal steroids. For example, it has been demonstrated that long-term increases in glucocorticoids (either through direct administration of corticosterone or through stress) produce morphological changes which are seen mainly in the CA3 hippocampal field, while being less evident or absent in the CA1 field and dentate gyrus [18,19,36,37,39]. On the other hand, the absence of adrenal steroids, such as could occur with adrenalectomy, produces cell death of dentate gyrus granule cells, having unnoticeable effects on hippocampal pyramidal cells [24,32,40]. The present study was designed to extend our previous observations in the DG, of adrenal steroid effects on plasticity, to the CA1 hippocampal field and more specifically to test for these effects ex vivo - in the hippocampal slice. Specific MR and GR agonists were administered to rats 1 h prior to slice preparation and LTP was tested in the CA1 field of slices using field potentials. The results indicate that similar to the DG, adrenal steroids exert a bimodal effect on LTP with MR activation enhancing it and GR activation suppressing it. Unlike the observation in the in vivo preparation, however, LTD was rarely observed in the CA1 field of slices. These results are consistent with previous observations of a suppression in LTP in CA1 field slices in animals with high-plasma corticosterone levels.

2. Experimental procedures 2.1. General methods Fifteen male Sprague-Dawley rats (Charles River Labs),

110-300 g at time of testing, were included in the study. Upon arrival, the animals were group housed and allowed a minimum of 3 days recovery from transport before they were used in the experiment. The animals were maintained in a temperature- (22°C) and light- (12:12 h light/dark cycle; lights on 07.00 h) controlled environment. Two to three days prior to the experiment, animals were either adrenalectomized (ADX) or sham ADX bilaterally under Nembutal anesthesia. Subsequently, the animals were kept in pairs in Plexiglas cages and were allowed ad libitum food and water, supplemented with 0.9% NaC1. On the day of the experiment, the animals were brought to the lab and injected (subcutaneously) with one of the following: Aldosterone (100 /xg/kg body weight); RU 28362 (100 / z g / k g body weight); or vehicle (propylene glycol). Sixty to 90 min later, the animals were anes-

thetized lightly with ethyl ether and hippocampal slices were prepared. 2.2. Slice preparation Following decapitation, the brain was quickly removed and placed in ice-cold ( - 4 ° C ) oxygenated artificial cerebrospinal fluid (aCSF) for approximately 2 min. The two hippocampi were then dissected and transverse, mid-dorsal, hippocampal slices (350-400 /xm thick) were prepared using a tissue chopper (Mcllwain). The slices were kept in aCSF at room temperature, in a holding chamber, which was continuously oxygenated (95% 02 and 5% CO2), for a minimum of 45 min. Three to four slices were then placed on a nylon net in an interface chamber (Fine Science Tools). The slices were superfused (2 m l / m i n ) continuously with oxygenated aCSF at 31.5-32.5°C, as well as being bathed constantly with humidified 95% 02 , 5% CO 2. The aCSF consisted of (in mM): NaC1 124.0, KC1 5.0, CaC1 2.4, MgSO 4 1.3, NaHCO 3 10, NaH2PO 4 1.25 and 10.0 glucose. At the conclusion of recording from a set of slices, a new batch of slices were placed on the recording chamber and recording was made from these. The longest time period between tissue preparation and recording was approximately 10 h. 2.3. Stimulation and recording Extracellular field potentials were recorded using 3 M NaCl-filled glass microelectrodes with tip resistances 1-2 M I2. Field excitatory post-synaptic potentials (fEPSPs) and population (pop) spikes were recorded by placing the recording electrodes 50-150 /~m ventral to surface in the CA1 pyramidal cell layer or stratum radiatum. Unipolar stimulating electrodes (etched, platinum-in-glass microelectrodes) were positioned slightly below the surface, either in stratum radiatum or in oriens (see Fig. 1). A silver coated wire in the bath served as return path for stimulation, reference for recording, and ground. Stimulation consisted of negative, rectangular current pulses 10-60 ~A, 100-200 /zs duration. Field potentials were triggered at 0.012 Hz, band-pass filtered (3 Hz - 3 kHz), amplified and digitized (SCXI sample-and-hold amplifier, National Instruments), averaged (5), analyzed on-line (custom built data acquisition and analysis software using LabView, National Instruments) and stored in a computer (Apple Macintosh). Field potentials were simultaneously displayed on a Tektronix 5223 digital, storage oscilloscope. Measurements were made of the EPSP slope and population spike (see Fig. 2). A maximum of three slices were accepted from any one animal for the final analysis of data, although in the majority of cases less than two slices were included. Three criteria were used to accept a slice for final analysis: (1) the field potentials had to be stable (i.e., fEPSP slope not to exceed 1 standard deviation from mean) for at least 10

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Fig. 1. Photomicrograph of hippocampal slice showing placement of recording electrode in the CA1 pyramidal cell layer and stimulating electrodes in radiatum (S1) and oriens ($2). Slices were placed in an interface type chamber at 32°C, continuously infused with regular aCSF. High-frequency stimulation was applied to one of the stimulating electrodes while the second served as control, to ensure stability of recording.

min of baseline; (2) at half maximum intensity, population spikes of at least 1 mV had to be evoked (although in the majority of cases population spikes of more than 2 mV were evoked); in the experiments in which stimulation was applied to a second input (as described below) the control, non tetanized pathway had to show stable potentials (fEPSP slope not exceeding 1 standard deviation from mean) throughout the recording period. In a number of experiments, stimulation was applied to a second independent input. This was done to ensure stable recording, especially

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5mV 5ms Fig. 2. Representative field potentials recorded in the hippocarnpal CA1 pyramidal cell layer of slices with stimulation of the Schaffer collaterals. These particular fEPSPs were recorded during baseline (dotted line) and after 200 Hz stimulation (filled line). Measurements were made of the fEPSP slope (a) and the population spike (b).

in testing for LTD. That is, the control input had to remain stable after HFS to the test input. This would insure that decrements in field potentials were not due to deterioration of the slice. Independence of the two inputs was determined using paired pulse stimulation of the two inputs. Stimulation was applied to the test input followed at various time intervals (ranging from 30 to 100 ms) with stimulation to the second input. The two inputs were said to be independent if paired-pulse facilitation/inhibition was not observed. Initially, a brief input-output function was determined using stimuli from minimum intensity for eliciting a field potential to an intensity required for eliciting maximum responses. A test stimulus was then chosen of an intensity sufficient to produce a population spike approximately 50% of maximum. Baseline recording was then made (minimum of 10 min), following which high-frequency stimulation (200 Hz, 50 ms, 5 times, at 5 s, at test stimulation intensity) was applied and recording continued for a minimum of 30 min to determine the effects of the HFS. Potentiation/depression was determined as percent change from baseline. In a number of cases, 100 Hz or 400 Hz stimulation, at similar parameters as above was also applied. The effects of such stimulation were analyzed separately from the main results. 2.4. Data analysis and statistics LTP was expressed as percent change from baseline. For the group results, the effects of drug injection on LTP

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were analyzed by one-way ANOVA followed by post hoc comparisons (Fisher multiple tests, c~ = 0.05). Statistical analysis was performed using the StatView (v. 4.01; Abacus Concepts) package on an Apple Macintosh microcomputer.

3. Results The averaged results are presented in Fig. 3. Highfrequency stimulation (200 Hz) in slices from control injected, non-ADX, animals produced an average increase of 33.7% (_+ 14.7% S.E.M., n = 3) of the fEPSP slope and 25.8% (_+6.2% S.E.M., n = 3) of the population spike. For the control ADX group, HFS (200 Hz) produced an average increase of 30.1% (_+ 7.4% S.E.M., n = 6) of the fEPSP and 22.4% ( _ 5.9% S.E.M., n = 6) of the population spike. Thus, comparable LTP was induced for the intact and ADX animals. For the comparisons of adrenal steroid effects, therefore, the ADX and intact (non-ADX) controls were combined. In comparison to the control groups, similar high frequency stimulation (200 Hz) in slices from animals in-

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jected with aldosterone produced higher, although not significant, increases of the fEPSP slope, 46.7% (_+ 16.9% S.E.M., n = 7, P = 0.28) and significant increases of the population spike, 54.6% ( + 9 . 3 % S.E.M., n = 7, P < 0.01). In contrast, high-frequency stimulation in the slices from animals injected with RU 28362 produced a significant suppression in LTP as measured by both the fEPSP slope, 5.9% (_+4.4% S.E.M., n = 8, P < 0.05) and the population spike 7.4% (_+ 4.6% S.E.M., n = 8, P < 0.05). We previously reported (in vivo, DG) that in a large number of animals ( 6 / 7 ) which had high plasma corticosterone levels or which were administered the GR specific agonist RU 28362, high-frequency stimulation (especially at 100 Hz), produced LTD instead of LTP, in comparison to ADX controls of which 1 / 5 showed LTD [23]. In this experiment, we tried to determine whether LTD could be induced in the CA1 field of slices. Similar to the previous study, none of the control slices (either from intact or ADX animals) showed LTD, with 200 Hz stimulation. However, none of the slices from the RU 28362 group showed significant LTD, either. In a different set of slices (not included in the main analysis; n = 4), high-frequency stimulation was applied at 100 Hz. In these, only one showed a small amount ( - 20.72%) of LTD of the population spike.

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Fig. 3. Averaged results of the effects of MR and GR activation on long-term potentiation. Measurements were made of the fEPSP slope and the population spike. High-frequency stimulation in the slices from control injected animals ( A D X + n o n - A D X control, n = 9) produced a moderate degree of potentiation (in comparison to baseline), as measured both for the fEPSP slope (31.0% ± 6.1% S.E.M.) and the population spike (23.5%_+4.3% S.E.M.). In comparison, similar stimulation in the slices from animals injected with aldosterone (n = 7) produced higher (approaching significance, P - 0 . 1 6 ) potentiation for the fEPSP slope (46.7%± 16.9% S.E.M.) and significantly higher potentiation for the population spike (54.6%±9.3% S.E.M.). In contrast, high-frequency stimulation in the slices from the RU 28362-injected animals ( n - 8 ) produced almost complete suppression in LTP as measured both fur the fEPSP slope (5.9% ± 4.4% S.E.M.) and the population spike (7.4% ± 4.6% S.E.M.). This potentiation was significantly lower ( P < 0.05) than the potentiation from control slices.

4. Discussion The present study revealed that synaptic plasticity in the form of long-term potentiation is affected by adrenal steroid manipulations in a similar direction in the CA1 hippocampal field, as had previously been shown in the dentate gyms [25]. Thus, while MR activation produced an enhancement of LTP in both regions of the hippocampal formation, GR activation produced a marked suppression. These findings are consistent with the fact that adrenal steroid receptors of both types are found throughout the trisynaptic circuit in both pyramidal neurons and dentate granule cells [11,17,21,27]. Experiments are currently under way to determine the effects of adrenal steroids and stress on LTP in the CA3 hippocampal field. Similar bimodal effects of corticosterone on LTP were also recently shown by Kerr et al. [15]. In this study, plasma corticosterone levels were manipulated in intact (non-ADX) rats by administration of corticosterone or metyrapone (a corticosterone protein synthesis inhibitor). Injections were made twice daily for two days and again 2 h prior to sacrifice. In a separate experiment, animals were either injected with both corticosterone and metyrapone or RU 28362 was applied directly to slices of metyrapone-injected rats. LTP and heterosynaptic LTD were tested in the CA1 field of hippocampal slices. Similar to the present study, slices from animals with high plasma corticosterone levels (which would presumably occupy GR), or from

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animals that were administered RU 28362, exhibited significantly lower LTP (and heterosynaptic LTD not tested in the present study) than slices from rats with moderate levels of plasma corticosterone. Reduced LTP was also observed in slices from animals with low plasma corticosterone. This observation is in contrast to the present experiment in which LTP in the slices from the ADX animals (which presumably had low plasma corticosterone levels) was not significantly lower than what was seen in slices from intact (non-ADX animals). In the Kerr et al. study, a number of slices from the low corticosterone, high corticosterone and RU 28362 injected group also showed homosynaptic LTD, instead of LTP. This last observation is similar to what we previously observed in the DG in vivo (i.e., LTD or depotentiation in animals with high plasma corticosterone levels, [25]); however, induction of LTD in the CA1 slices was not readily or frequently induced. This is not surprising since LTD induction is usually more difficult to accomplish in slices, perhaps reflecting a reduction in inhibition. Besides being confirmatory to the present results, the Kerr et al. study is also of significance in that the adrenal steroid manipulations were performed in intact (i.e., non-ADX) animals and, therefore, adrenal catecholamines, opioid peptides and ACTH should not have been affected. The present results are also in agreement with previous findings by Diamond and collaborators. In an early study it was reported that plasma corticosterone levels showed a linear negative correlation with PBP in the CA1 hippocampal field, in vivo [1]. In a later study, however, it was demonstrated in the CA1 hippocampal field, in vivo, that the relationship between plasma corticosterone and PBP more closely resembled an inverted-U function between plasma corticosterone and PBP in the CA1 hippocampal field of intact animals [7]. Thus, enhanced PBP was observed in animals with intermediate ( ~ 12 /xg/dl) plasma corticosterone with lower and higher levels producing suppressed levels of PBP. These effects can thus be assumed to be due to differential activation of MR and GR. A number of studies have also reported a reduction in synaptic plasticity as a result of stress. Originally, Foy et al. [10] showed that an acute episode of stress suppressed LTP in the CA1 field of hippocampal slices. A number of later studies, from the same laboratory, showed similar results [28,30,31]. Animals exposed to a novel environment, a stressful stimulus for rats, also showed deficits in synaptic plasticity [8,9]. Most of these studies also reported a negative correlation between plasma corticosterone and synaptic plasticity. Although originally it was thought that the stress-induced suppression in LTP was due to the effects of adrenal steroids, later evidence [29] indicated that these effects are probably due to changes in opioid peptides, since adrenalectomy did not completely account for the stress-induced reductions (which were also not restored by corticosterone replacement). On the other hand, stress in demedullated rats, which allows for the normal

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increase in corticosterone but eliminates the synthesis and release of catecholamines and opioid peptides, did not result in further decrements in LTP. A later study also showed that the stress-induced reduction in LTP could be prevented by Naltrexone, an opioid peptide antagonist. These data collectively suggest that the stress-induced effects on LTP are probably subserved by opioid peptides. There may be a number of problems with this hypothesis, however, since: (1) it is possible that the reductions in LTP by stress were partially brought about by corticosterone; (2) opioid peptide dependent LTP has only been shown to occur in the mossy fiber to CA3, and lateral perforant path to DG and CA3 inputs [4-6,20,33,34,38,41]. At present, all the evidence suggests that LTP in the CA1 hippocampal field is not dependent or modulated by opioid peptides (for review see [3]). Although this hypothesis is still viable, stronger supportive evidence will be required. A critical question that arises concerns the possible mechanisms underlying the adrenal steroid effects on LTP (and whether adrenal steroid and stress-induced modulation of LTP share common mechanisms). A number of studies investigating the effects of adrenal steroids on neuronal excitability by JoEls et al. and Kerr et al. may shed light on these questions. Using intracellular recordings from CA1 pyramidal cells it was demonstrated that MR and GR affect the afterhyperpolarization (AHP), that follows action potentials, in these neurons in opposite directions [12,14]. That is, MR activation decreases and shortens the time course of the AHP while activation of the GR increases it and prolongs it (for review see [13]). These effects of adrenal steroids on the AHP could perhaps explain their effects on LTP. It is well known that in the DG and CA1 hippocampal fields the induction phase of LTP is dependent on activation of voltage-sensitive NMDA receptors (for review see [2]). According to this model, each stimulus within a high frequency train produces further depolarization which in turn leads to an influx of calcium, which then leads to an enhancement in synaptic transmission. An increase and prolongation of the AHP, as occurs with GR activation, would reduce the amount of depolarization HFS would produce thus decreasing or preventing LTP induction. Conversely, activation of MR, with aldosterone or low levels of corticosterone, would in effect allow for more depolarization during the HFS and thus more LTP. Although the different hippocampal subfields (i.e., the dentate gyms and CA1 field) are similar with respect to synaptic plasticity, they nonetheless show different susceptibilities to MR and GR activation. In the dentate gyms, MR occupancy by aldosterone appears to prevent adrenalectomy-induced cell death, whereas GR occupancy by RU 28362 is not effective [40]. Cell death after adrenalectomy was not seen in the CA1 region. MR activation by aldosterone was effective in suppressing ADX-induced increases in neuropeptide-Y mRNA in the hilus of the dentate gyrns [35] as well as suppressing ADX-induced

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i n c r e a s e s in 5-HTIA r e c e p t o r b i n d i n g in the C A 3 r e g i o n a n d d e n t a t e g y m s o f the h i p p o c a m p u s [16]; R U 2 8 3 6 2 w a s ineffective on these gene products. T h e fact that t h e effects o f a d r e n a l steroid a c t i v a t i o n w e r e p r o d u c e d in v i v o in a d r e n a l e c t o m i z e d rats a n d t h e n s t u d i e d e x v i v o in t h e slice p r e p a r a t i o n d e m o n s t r a t e s that a d r e n a l steroid e f f e c t s are l o n g - l a s t i n g , p r o b a b l y g e n o m i c , a n d p e r s i s t in the slice p r e p a r a t i o n . T h i s s h o u l d s e r v e as a w a r n i n g to p e o p l e p e r f o r m i n g L T P studies in h i p p o c a m p a l slices, in that t r e a t m e n t or h a n d l i n g o f the a n i m a l s p r i o r to slice p r e p a r a t i o n c o u l d s i g n i f i c a n t l y affect the L T P results,

Acknowledgements T h e a u t h o r s w i s h to t h a n k P r o f e s s o r s H. A s a n u m a a n d J. W i n s o n for t h e i r c o n t i n u e d support. C.P. is also m o s t g r a t e f u l to Drs. H e l e n S c h a r f m a n a n d P a t r i c k S t a n t o n for t h e i r h e l p w i t h e s t a b l i s h i n g a slice p r e p a r a t i o n . R U 2 8 3 6 2 was a generous donation from Rousel-Uclaf, France. F u n d e d b y a W h i t e h a l l F o u n d a t i o n g r a n t to C.P., U S A F C o n t r a c t A F S C # F 4 9 6 2 0 - 9 3 - 1 - 0 0 4 8 to B . S . M . a n d C.P., a n d N I H G r a n t M H 4 1 2 5 6 to B . S . M .

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