Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats

Brain Research Bulletin 85 (2011) 374–379

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Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats Wen Hu a , Mingyue Zhang c , Boldizsár Czéh a,1 , Weiqi Zhang c , Gabriele Flügge a,b,∗ a b c

Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany DFG Research Center Molecular Physiology of the Brain (CMPB), University of Göttingen, Germany Laboratory of Molecular Psychiatry, Department of Psychiatry, Westfälische Wilhelms University, Münster, Germany

a r t i c l e

i n f o

Article history: Received 3 November 2010 Received in revised form 29 March 2011 Accepted 12 April 2011 Available online 16 April 2011 Keywords: Chronic stress GABA Endocannabinoid DSI Neuroplasticity

a b s t r a c t Chronic stress, a risk factor for the development of psychiatric disorders, is known to induce alterations in neuronal networks in many brain areas. Previous studies have shown that chronic stress changes the expression of the cannabinoid receptor 1 (CB1) in the brains of adult rats, but neurophysiological consequences of these changes remained unclear. Here we demonstrate that chronic restraint stress causes a dysfunction in CB1 mediated modulation of GABAergic transmission in the hippocampus. Using an established protocol, adult male Sprague Dawley rats were daily restrained for 21 days and whole-cell voltage clamp was performed at CA1 pyramidal neurons. When recording carbachol-evoked inhibitory postsynaptic currents (IPSCs) which presumably originate from CB1 expressing cholecystokinin (CCK) interneurons, we found that depolarization-induced suppression of inhibition (DSI) was impaired by the stress. DSI is a form of short-term plasticity at GABAergic synapses that is known to be CB1 mediated and has been suggested to be involved in hippocampal information encoding. Chronic stress attenuated the depolarization-induced suppression of the frequency of carbachol-evoked IPSCs. Incubation with a CB1 receptor antagonist prevented this DSI effect in control but not in chronically stressed animals. The stress-induced impairment of CB1-mediated short-term plasticity at GABAergic synapses may underlie cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders. © 2011 Elsevier Inc. All rights reserved.

1. Introduction Stress can facilitate the development of psychiatric disorders in genetically predisposed individuals. Preclinical studies document that chronic stress results in marked alterations in neuronal morphology and physiology in various limbic and cortical brain areas which mediate behavioral effects of stress. Such stress-induced processes may contribute to the pathophysiology of mood disorders [6,18,23]. Increasing evidences suggest that central nervous endocannabinoids play a role in stress responses. Genetic disruption of endocannabinoid signaling by knocking out the cannabinoid receptor 1 (CB1 receptor) increased activity of the hypothalamic–pituitary–adrenal (HPA) axis, sensitized ani-

∗ Corresponding author at: Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077 Göttingen, Germany. Tel.: +49 551 3851 133; fax: +49 551 3851 307. E-mail address: gfl[email protected] (G. Flügge). 1 Current address: Molecular Neurobiology, Max-Planck-Institute of Psychiatry, Munich, Germany. 0361-9230/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2011.04.005

mals to stress and promoted passive coping behavior [7,29,30]. Furthermore, hippocampal CB1 receptor expression [12,26] and CB1 binding capacity [10] have been reported to be altered due to chronic stress. Several studies using different stress paradigms with different rodent species consistently showed that chronic stress regulates the endocannabinoid content in distinct brain areas and that the stress-induced changes are model-dependent [12,21,24]. In addition, neurophysiological studies revealed altered CB1 receptor activity following stress. Repeated restraint (homotypic) stress enhanced short-term endocannabinoid signaling at inhibitory synapses in the basolateral amygdala [21], and chronic emotional stress impaired cannabinoid receptor mediated control of GABA transmission in the striatum [27]. Deficient endocannabinoid signaling in the hippocampus was supposed to cause impaired reversal learning after chronic stress [12] whereas increased endocannabinoid signaling in the amygdala may facilitate habituation to restraint stress [11,22]. In humans, genetic variations in the CB1 gene (CNR1) have been reported to be associated with vulnerability to stressful life events and with the development of depressive symptoms [14]. CB1 receptors in the hippocampus are localized on the axon terminals of a specific subtype of GABAergic cells, the neuropeptide

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2. Materials and methods 2.1. Animals and chronic restraint stress Group housed (3–4 animals/cage) adult male Sprague Dawley rats (n = 14; Harlan Winkelmann, Borchen, Germany) weighing 170–200 g (age 6–7 weeks) at the beginning of the experiment were used. The experiments were performed in accordance with the European Communities Council Directive of November 24, 1986 (86/EEC) and the US National Institutes of Health Guide for the Care and Use of Laboratory Animals, and were approved by the Lower Saxony Federal State Office for Consumer Protection and Food Safety, Germany. Animals were kept under an inverse light cycle (light off from 7:00 AM to 7:00 PM), and all experimentation including daily weighing and handling of controls was performed under dimmed red light to not disturb the circadian rhythm of the animals. Animals of the chronic stress group were restrained daily for 6 h (from 8:00 to 14:00 which is during their active period) for a total of 21 days according to an established protocol [19]. Animals were sacrificed in the morning following the last stress exposure. During restraint, animals were not physically compressed and did not experience pain but had no access to food and water. Food and water was also withheld from the controls during the restraint period to ensure that effects of the experimental procedure were not simply a result of limited food availability. Throughout the entire experiment, body weight was recorded daily in the morning, prior to the onset of restraint.

6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 40 ␮M NMDA antagonist 2-amino5-phosphonovaleric acid (APV) and 1 ␮M glycine receptor antagonist strychnine to block glutamatergic and glycinergic transmission, respectively. Signals with amplitudes at least twofold above the background noise were analyzed. There were no significant differences in noise levels between control and stress animals. Patches with a serial resistance of >20 M, a membrane resistance of <0.8 G, or leak currents of >150 pA were excluded. The membrane currents were filtered by a four-pole Bessel filter at a corner frequency of 2 kHz, and digitized at a sampling rate of 5 kHz using the DigiData 1322A interface (Axon Instruments/Molecular Devices, Sunnyvale, CA, USA). Data acquisition was performed using commercially available software (pClamp 10.1; Axon Instruments/Molecular Devices, Sunnyvale, CA, USA). MiniAnalysis 6.0.9 (Synaptosoft Inc., Decatur, GA, USA) was used for amplitude and frequency analysis of IPSC frequencies. The mACh agonist carbachol and the CB1 receptor antagonist/inverse agonist AM251 were obtained from Sigma–Aldrich (Sigma–Aldrich, St. Louis, MO, USA). DSI was initiated by a single 5 s-depolarizing voltage step from −70 mV to 0 mV. All DSI tests were conducted at least 3 min after achieving a stable whole-cell configuration, and three DSI tests were applied to each cell. The effect of DSI was calculated as the ratio of carbachol-induced IPSC frequency after to that before depolarization.

2.3. Statistical analysis Data are presented as mean ± SEM. Data on the effect of depolarization were analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test. Effects of stress and drug were analyzed by repeated two-way ANOVA.

3. Results To assess whether the restraint stress procedure was effective, body weights were recorded daily throughout the experiment [17,18]. Chronic restraint significantly decreased body weight gain as demonstrated with two-way ANOVA revealing a significant main effect of stress (stress × time, F1,32 = 15.47, P < 0.0001; n = 7 per group; Fig. 1). As previously reported, bath application of 5 ␮M carbachol induces rhythmic IPSCs which are dramatically suppressed by both CB1 stimulation [15] and postsynaptic depolarization [25]. In our experiment, a single 5 s-depolarizing voltage step significantly reduced the carbachol-induced IPSCs (Fig. 2A). In control rats, the 10 s-averaged IPSC frequency immediately after depolarization was only 58.6 ± 6.5% of that before depolarization (P < 0.001, one way ANOVA followed by Dunnett’s multiple comparison test; Fig. 2C1), and similarly, the IPSC amplitude was reduced to 55.4 ± 7.8% of the level before depolarization (P < 0.001; Fig. 2C2). Suppression of the IPSC frequency sustained even 2 min after depolarization (normalized 10 s-averaged IPSC frequency: 67.2 ± 8.3%; P < 0.001, one way ANOVA followed by Dunnett’s multiple comparison test; Fig. 2C1).

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cholecystokinin (CCK) containing interneurons [8]. A presynaptic localization of CB1 receptors at glutamatergic synapses has also been observed [5,16]. By contrast, these receptors have been reported to be absent from the inhibitory synapses of other interneuron subtypes as revealed by immunocytochemistry [8]. Several studies identified endocannabinoids as important retrograde neurotransmitters which predispose CB1 expressing interneurons to activity-dependent modulation of GABA release. Specifically in the hippocampus, endocannabinoids such as 2arachidonoylglycerol (2-AG) are mobilized from postsynaptic pyramidal cells either by a rise in Ca2+ influx or by mGluRs signaling. Furthermore, endocannabinoids modulate hippocampal GABAergic transmission through depolarization-induced suppression of inhibition (DSI), presumably via the CB1 receptors on CCK interneurons [15], and they interrupt theta-rhythm IPSCs evoked by stimulation of muscarinic acetylcholine receptors [25]. The functional significance of DSI is yet to be understood, however, it has been proposed that DSI contributes to information encoding in the hippocampus [25]. Activation of CB1 receptors was reported to interfere with hippocampal network oscillations. This mechanism is believed to provide a temporal structure necessary for neurotransmission underlying cognitive processes such as representation and information transfer, memory storage and retrieval [1,28]. Localized DSI may disinhibit single pyramidal neurons and possibly also their neighboring cells allowing them to transiently escape from synchronized network oscillations and to become more susceptible to the induction of long-term potentiation [3,25]. We recently showed that chronic restraint stress affects the hippocampal GABAergic network via changes in the temporal precision of one type of inhibitory cells, the parvalbumin expressing perisomatic interneurons. In contrast, the carbachol-evoked rhythmic activity which is presumably mediated via CCK interneurons was not affected by the stress [13]. In the present study, we recorded GABAergic transmission at CA1 pyramidal neurons while glutamatergic transmission was blocked. Our data demonstrate that chronic restraint stress impairs DSI which is mediated via CB1 receptors expressed in the CCK interneurons.

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2.2. Whole-cell recordings and DSI Whole-cell voltage-clamp recordings were performed in acute coronal hippocampal slices (350 ␮m thickness) from CA1 pyramidal neurons of the dorsal hippocampus. The bath solution in all experiments consisted of 125 NaCl, 2.5 KCl, 1.25 Na2 HPO4 , 2 MgSO4 , 26 NaHCO3 , 1.5 CaCl2 , 1 ascorbic acid, 14 glucose (in mM) (pH 7.4, aerated with 95% O2 – 5% CO2 ) and kept at 30 ◦ C. The pipette solution for all experiments contained 140 KCl, 1 CaCl2 , 10 EGTA, 2 MgCl2 , 0.5 Na2 –GTP, 4 Na2 –ATP, 10 HEPES (in mM); pH was adjusted to 7.2 with KOH. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded at a holding potential of −70 mV in the presence of 10 ␮M AMPA antagonist

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days Fig. 1. Body weight as parameter demonstrating the physiological response to chronic stress. Chronic restraint stress significantly decreased body weight gain. Data are mean ± SEM; n = 7 per group. Significant difference between groups as determined by repeated two-way ANOVA (stress × time): F1,32 = 15.47, P < 0.0001.

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Fig. 2. Chronic stress impairs endocannabinoid mediated suppression of interneuron activity. (A and B) Representative recordings of carbachol-induced IPSCs of a CA1 pyramidal neuron from a control (A) and a chronically stressed animal (B) before and after depolarization. (C) Time course of the DSI effect on carbachol-induced IPSC frequency (C1) and amplitude (C2) (graphs show relative changes). In the control group, a single 5 s-depolarizing voltage step significantly reduced the frequency of carbachol-induced IPSCs whereas in the chronic stress group, the effect of depolarization on carbachol-induced IPSCs was attenuated. Data are mean ± SEM; n = 7/group; significant differences as determined by repeated two-way ANOVA, **P < 0.01.

In the chronically stressed animals, the frequency of the carbachol-induced IPSCs was resistant to DSI (Fig. 2B and C1). Repeated two-way ANOVA revealed a significant main effect of stress (F1.66 = 15.08, P = 0.0025). In contrast, the amplitude of the carbachol-induced IPSCs in the chronically stressed animals was not resistant to DSI (Fig. 2B and C2). Repeated two-way ANOVA showed no significant difference between the amplitudes in control and stressed rats (F1.66 = 0.024, P = 0.8808; Fig. 2C2). In the control animals, the depolarization-induced suppression of the carbachol-induced IPSCs was completely abolished by a 15 min incubation with the CB1 antagonist/inverse agonist AM251 (10 ␮M) with respect to both frequency and amplitude (frequency: drug × time F(1,66) = 19.24, P = 0.0011; amplitude: F(1,66) = 6.10, P < 0.05; repeated two-way ANOVA; Fig. 3A, C1 and C2). This confirms that the DSI effect was mediated by CB1 receptors. In contrast, in the slices from the stressed animals, where DSI had no effect on the carbachol-evoked IPSC frequency, AM251 induced no change. Both frequency (repeated two-way ANOVA drug × time, F1,72 = 0.17, P = 0.6906; Fig. 3B and D1) and amplitude showed no significant differences between the recordings with and without AM251 (repeated two-way ANOVA drug × time, F1,72 = 0.089, P = 0.7709; Fig. 3B and D2). 4. Discussion The above data demonstrate that chronic stress impairs the endocannabinoid mediated modulation of GABAergic transmission in the hippocampus. We provide new experimental evidence for neurophysiological consequences of the chronic stress-induced

disturbances of endocannabinoid signaling that had been detected before in this brain region [12]. To selectively record GABA neurotransmission in our experimental set up, we blocked glutamatergic transmission. Because hippocampal CB1 receptors are expressed on CCK interneurons, the stress-induced impairment of DSI suggests an altered functional integrity of the CCK interneuron network. We show that three weeks of daily restraint stress attenuated the depolarization-induced suppression of carbachol-evoked IPSCs at CA1 pyramidal neurons. Similar to this, five days of daily restraint stress attenuated DSI of evoked IPSCs in the hypothalamic paraventricular nucleus of juvenile male Sprague Dawley rats, whereas a single or only three days of immobilization stress had no effect in these animals [31]. It thus appears that chronic stress affects DSI in different brain regions and at different ages, respectively. The present DSI effect was prevented by the CB1 antagonist/inverse agonist AM251 which supports the view that DSI is CB1 receptor mediated. However, in the hippocampal slices from the chronically stressed animals, AM251 failed to abolish the effect of the postsynaptic depolarization indicating that chronic stress impairs CB1 receptor functioning. This coincides with data showing that in the striatum of male mice, three or seven days of social defeat stress eliminated the CB1 mediated inhibition of IPSCs [27]. The interpretation that the present stress effect is caused by impaired CB1 receptor signaling is supported by data showing that at least chronic unpredictable stress downregulates hippocampal CB1 receptors [12]. Furthermore, in the basolateral amygdala of male mice, ten days of daily restraint stress (1 h per day) diminished CB1 receptor sensitivity, in this case documented by a reduced CB1 mediated suppressing of evoked IPSCs [21].

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Fig. 3. Depolarization-induced suppression of inhibition (DSI) is mediated by endocannabinoid signaling. (A and B) Representative recordings of carbachol-induced IPSCs of a CA1 pyramidal neuron from a control (A) and a chronically stressed animal (B) in the presence the CB1 antagonist/inverse agonist AM251, before and after depolarization. (C) Time course of the DSI effect on carbachol-induced IPSC frequency (C1) and amplitude (C2) (graphs show relative changes). (C1 and C2) DSI in the control group was abolished in the presence of the CB1 antagonist/inverse agonist AM251. (D1 and D2) AM251 incubation had no significant effects in the slices from chronically stressed animals. Data are mean ± SEM, n = 7/group. Significant differences as determined by repeated two-way ANOVA, **P < 0.01.

Receptor downregulation may not be the only cause for the stress-induced attenuation of DSI as deficits in mobilization of endocannabinoids following depolarization might also result in the observed changes [11,12]. For the study on the basolateral amygdala of male mice, following a nine days period of daily immobilizations, brain samples were taken directly after the last stress exposure, that is immediately after 20 or 60 min of immobilization in the restraining tube ([21] and personal communication). Under these experimental conditions, the concentration of the endocannabinoid 2-AG in the amygdala of the mice was increased in the stress group, probably reflecting an acute endocannabinoid mobilization during the stress exposure [21]. Also in the amygdala of male Sprague Dawley rats, the concentration of 2-AG was increased after chronic restraint stress, at least in the samples that were taken at 30 min of the last stress exposure [11]. Another endocannabinoid, anandamide, was decreased in the hippocampus like in other corticolimbic structures, and authors emphasized that there is a divergent regulation of the two endocannabinoids, 2-AG and anandamide [11]. These data may indicate that chronic restraint stress reduces at least anandamide concentrations in the hippocampus. However, the brain samples used for determination

of this endocannabinoid were taken shortly after the restraint stress session, whereas in the present study hippocampal slices were analyzed in the morning after the last stress exposure. Since in a study using another stress paradigm, chronic unpredictable stress in male Long-Evans rats, hippocampus samples taken also at least 12 h after the last stress exposure, 2-AG and CB1 receptor protein were both found to be decreased, one may assume that both mechanisms, CB1 receptor downregulation and reduced endocannabinoid mobilization play a role in stress-induced DSI deficits [12]. It has been reported that there is a cross talk between endocannabinoids and glucocorticoids which are increased during stress due to persistent HPA axis hyperactivity [2,4]. This cross talk may contribute to enhanced endocannabinoid activity following stress within hypothalamus and amygdala [2,4,31]. Interestingly, the chronic social stress-induced impairment of CB1 mediated signaling in the striatum of male mice was prevented by pharmacological blockade of glucocorticoid receptors and mimicked by chronic corticosterone injections [27]. A similar association between the loss of CB1 mediated signaling and corticosterone action was also observed in the hypothalamus [31]. In the rat hippocampus, the density of CB1 receptors was downregulated by prolonged

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glucocorticoid treatment [9]. Because during chronic stress glucocorticoid secretion is persistently increased, it is likely that the negative regulation of CB1 receptors by glucocorticoids contributes to the stress-induced disruption of hippocampal endocannabinoid signaling. However, further investigations are necessary to elucidate the exact mechanisms of stress and glucocorticoids regulating the endocannabinoid system. In the present study, the depolarization-induced suppression of the carbachol-evoked IPSC frequency was impaired by chronic restraint stress while the IPSC amplitude remained unaffected. This indicates a depolarization-induced, CB1 independent retrograde signaling mechanism which was activated by the prolonged stress. The nature of this phenomenon and how chronic stress may induce its occurrence are yet to be identified. In this context it is interesting to note that cannabinoids can modulate hippocampal excitatory transmission by directly blocking N-type voltage-gated Ca2+ channels [20]. Moreover, it has been shown that glutamatergic transmission in the hippocampus may also be regulated by presynaptic CB1 [5,16]. Future studies are necessary to determine whether the effects of chronic stress on CB1 regulated neurotransmission are limited to GABAergic synapses or involve also glutamatergic synapses. With respect to functional implications, it still remains unknown whether and how these neurophysiological processes contribute to the behavioral and/or the emotional effects of chronic stress. However, it has been suggested that downregulation of hippocampal endocannabinoid signaling plays a role in mechanisms underlying behavioral flexibility and other aspects of stress-related behavior [12]. Cognitive functions and memory processes, which supposedly depend on network oscillations that create a temporal structure for information processing, contribute to the abilities of coping with stress [1,18]. CCK interneurons in the hippocampus, which together with the PV interneurons provide perisomatic inhibition to the pyramidal neurons, are considered to play a pivotal role in the generation of oscillatory network activity. Because CB1 receptor activation interferes with hippocampal network oscillations it is very likely that endocannabinoids contribute to information encoding by affecting CCK interneurons which have to be recruited for oscillatory activity [8]. Furthermore, electrophysiological evidence suggests that endocannabinoid signaling, by inducing DSI, allows local pyramidal cells to escape oscillatory entrainment and to thus become more sensitive to LTP induction [3]. 5. Conclusions Taken together, the impaired endocannabinoid-mediated modulation of CCK interneuron activity presented here provides further insight into the neuroplastic changes which are induced by chronic stress. Our neurophysiological data show that three weeks of daily restraint stress in male Sprague Dawley rats attenuated the depolarization-induced suppression of the frequency of carbacholevoked IPSCs. The CB1 receptor antagonist/inverse agonist AM251 prevented the effect of depolarization on carbachol-evoked IPSC frequency and amplitude in control animals. In contrast, in stressed animals, where IPSC frequency was resistant to DSI, AM251 had no effect. The IPSC amplitude in the stressed animals, being suppressed by depolarization, was also not affected by AM251. We suggest that the stress-induced alterations in functioning of the inhibitory hippocampal network contribute to the cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders. Disclosure statement No author of this paper has a conflict of interest to declare.

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