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Contents lists available at ScienceDirect

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Research report

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Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression

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Hui Qiao a , Shu-Cheng An a,∗ , Wei Ren a , Xin-Ming Ma a,b a b

College of Life Science, Shaanxi Normal University, Xi’an, Shaanxi Province 710062, PR China University of Connecticut Health Center, Department of Neuroscience, Farmington, CT 06030, USA

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Studied the time course changes in synaptic plasticity during CUMS. No changes were observed at day 7 after the onset of 21-day CUMS. Abnormal synaptic transmission and some depressive-like behaviors were found at day 14. Depressive-like behaviors, functional and structural changes were found at day 21. The roles of Kalirin-7 and BDNF in synaptic plasticity during CUMS are discussed.

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Article history: Received 3 November 2013 Received in revised form 8 August 2014 Accepted 20 August 2014 Available online xxx

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Keywords: Synaptic plasticity Dendritic spine Kalirin-7 BDNF Stress

Major depressive disorder is the most prevalent psychiatric condition, but the cellular and molecular mechanisms underlying this disorder are largely unknown, although multiple hypotheses have been proposed. The aim of this study was to characterize the progressive alteration of neuronal plasticity in the male rat hippocampus during depression induced by chronic unpredictable mild stress (CUMS), an established animal model of depression. The data in the hippocampus were collected on days 7, 14 and 21 after the onset of three-week CUMS. When analyzed on day 21, three-week CUMS induced typically depressive-like behaviors, impaired LTP induction, and decreased basal synaptic transmission at hippocampal CA3-CA1 synapses recorded in vivo, which was accompanied by decreased density of dendritic spines in CA1 and CA3 pyramidal neurons. The levels of both Kalirin-7 and brain-derived neurotrophic factor (BDNF) in the hippocampus were decreased at the same time. On day 14 (middle phase), some depressive-like behaviors were observed, which was accompanied by depressed basal synaptic transmission and enhanced LTP induction at the CA3-CA1 synapses. However, BDNF expression was decreased without alteration of Kalirin7 expression in comparison with no-stress control. Depressed basal synaptic transmission occurred in the middle phase of CUMS may contribute to decreased expression of BDNF. On day 7, depressive-like behaviors were not observed, and LTP induction, spine density, Kalirin-7 and BDNF expression were not altered by CUMS in comparison with no-stress control. These results showed that the functional changes at CA3-CA1synapses occurred earlier than the structural alteration during threeweek CUMS as a strategy of neural adaptation, and rats required three weeks to develop depressive-like behaviors during CUMS. Our results suggest an important role of Kalirin-7 in CUMS-mediated alterations in spine density, synaptic function and overall depressive-like behaviors on day 21. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Abbreviations: CUMS, chronic unpredictable mild stress; BDNF, brain-derived neurotrophic factor; fEPSP, field excitatory postsynaptic potential; I/O curve, input–output curve; HFS, high-frequency stimulation; LTP, long term potentiation; ANOVA, analysis of variance. Q2 ∗ Corresponding author at: Mailbox 100, 620 West Chang’an Street, Shaanxi Normal University, Xi’an, Shaanxi Province 710119, PR China. Tel.: +86 13809195616; fax: +86 02985310623. E-mail address: [email protected] (S.-C. An).

Depression, a severe psychiatric disorder, is characterized by anhedonia, low self-esteem, fatigue, and feelings of worthlessness [1,2]. Major depression affects approximately 7% of the population in the US [3]. Although depression has been studied for decades, its cellular and molecular mechanisms still remain largely unknown [4]. Therefore, it is important to identify the mechanisms underlying depression in order to develop effective clinical intervention

http://dx.doi.org/10.1016/j.bbr.2014.08.040 0166-4328/© 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: Qiao H, et al. Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.08.040

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strategies. Depression is closely associated with selective structural changes, altered cellular resilience, and neuronal atrophy of the hippocampus [4–8]. Antidepressants have reversed these structural changes observed in animal models of depression [6,9,10]. These studies have generated the neural plasticity hypothesis of depression [11,12]. Dendritic spines are cellular substrates of brain connectivity and the major sites of information processing in the brain [13]. Dendritic spine pathology is associated with many mental disorders [14–16]. Loss of dendritic spines and retraction of apical dendrites of hippocampal CA3 pyramidal neurons have been documented in chronically stressed animals and postmortem tissue of depressed subjects [5,7,17–20], but the effects of chronic stress and depression on CA1 pyramidal neurons are less well characterized. One of our aims was to address the time course changes of dendrite spine density in CA1 pyramidal neurons during chronic unpredictable mild stress (CUMS), an animal model of depression. The functional consequences of the above morphological changes induced by chronic stress or depression are poorly understood, and the molecular mechanisms through which chronic stress or depression reduces spine density remain to be elucidated. Cytoskeletal proteins may be a particularly important element of the etiology of depression. Kalirin, a Rho-guanine nucleotide exchange factor, plays a pivotal role in the formation of dendritic spines and synaptic plasticity [21,22]. Reduced endogenous kalirin expression causes a decrease in spine density and the simplification of dendritic branching in CA1 pyramidal neurons [22,23]. Electroconvulsive therapy (ECT), an effective treatment for drug-resistant depression, causes an increase in kalirin levels in the rat hippocampus (ECT is called electroconvulsive shock when used in animal) [24]. Kalirin-7 is the major isoform of kalirin in the adult brain. Overexpression of Kalirin-7 increases, while reduced endogenous Kalirin-7 expression decreases spine density and synapse number in hippocampal neurons in vitro and in vivo [21,25–27]. These findings raise a hypothesis that kalirin7 is involved in the stress- and depression-mediated structural plasticity in the hippocampus. Ample evidence indicates that brain-derived neurotrophic factor (BDNF), playing a role in synaptic plasticity and in the establishment of long-term memory, may play a critical role in the development of depression [28,29]. Stress decreases the expression of BDNF [28], and antidepressant drugs and ECT reverse this decrease in the hippocampus in animal models of depression [29,30] and in postmortem hippocampus of patients with major depressive disorder [31,32]. The neurotrophic hypothesis of depression postulates that low levels of BDNF lead to specific functional and structural alterations, and ultimately induce depression [28,29,33]. Acute and chronic stress has the opposite effects on neuronal plasticity. The neuronal response to acute stress is important for survival whereas the long-term response to chronic stress can be detrimental. Chronic stress is believed to be a prominent cause of depression. Acute stress increases dendritic spine density in rat CA1 pyramidal neurons and enhances LTP in the hippocampus [34,35], while chronic stress decreases spine density and cause hippocampal CA3 dendrite atrophy [5,7,17,20,36]. The morphological and physiological alterations observed after chronic stress may represent a neuroadaptive consequence rather than a rapid modification of structure due to stress exposure [37]. The whole brain undergoes different changes based on the timing and length of the adverse experience. Although CUMS has been used widely to study depression and evaluate the antidepressant effects of diverse drugs [38–40], the progressive alterations of neuronal plasticity in the brain induced by CUMS have not been reported. This study was designed to address the time course of alterations of neuronal plasticity in the hippocampus during three-week CUMS by analyzing LTP at CA3-CA1 synapses, spine density in CA1 and CA3

Table 1 Time schedule of chronic unpredictable mild stress (CUMS). Day

Stressor and duration

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Inversion of the light/dark cycle for 12/12 h; Swimming in 4 ◦ C cold water or 5 ◦ C hot water for 5 min; Caged with damp sawdust for 24 h; Cage tilting for 24 h; Shaking for 5 min; Nip tail for 1 min; Fasting and water deprivation at the same time for 23 h + 1 h sucrose preference test.

pyramidal neurons, and expression of Kalirin-7 and BDNF expression in the hippocampus. We found that the CUMS-mediated alteration of synaptic function occurred earlier than the CUMSmediated structural changes and depressive-like behaviors, and Kalirin-7 and BDNF may be involved in these alterations.

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2. Materials and methods

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The animal protocol of the study was approved by national legislations of China and local guidelines. The investigation was conducted in accordance with the ethical principles of animal use and care. Adult male Sprague-Dawley rats, weighing 250–280 g, were purchased from Shaanxi Academy of traditional Chinese Medicine. The rats were kept on a 12 h light/12 h dark cycle with free access to food and water. After adaptation to the laboratory conditions for seven days, the animals were randomly divided into four groups. Three groups (n = 32 in 7th and 21st day groups, respectively and n = 40 in 14th day group) received chronic stresses, and the control group was handled daily without receiving any stress (n = 35). The time schedule is shown in Fig. 1. 2.2. Chronic unpredictable mild stress (CUMS) The CUMS procedure followed our previously described strategy and depressive-like behaviors are induced in rodents by this CUMS protocol [38–40]. In brief, the rats were individually kept (one rat/cage) and received one of following different stressors each day (Table 1): cage tilting for 24 h, swimming in 4 ◦ C cold water for 5 min, swimming in 45 ◦ C hot water for 5 min, caged with damp sawdust for 24 h, fasting for 24 h, water deprivation for 24 h, shaking for 5 min, nip tail for 1 min, and inversion of the light/dark cycle for 24 h. Rats received one of these stressors per day in the sequence shown in Table 1 and the same stressor was not applied in two consecutive days. For three CUMS groups, animals received one, two and three-week CUMS, respectively prior to behavioral testing, and the stress procedure was ended by food and water deprivation for 23 h at the same time as the final stressor. 2.3. Behavioral tests Rats were placed in the holding room 30 min before behavioral tests. All tests were performed in a soundproof room between 8:00 am and 1:00 pm, unless otherwise stated. After each test, rats were immediately returned to their home cages. All these behavioral tests were conducted in the same animals, and the order of the tests was: (1) sucrose preference test; (2) open field test; (3) elevated plus maze test; (4) tail suspension test. 2.3.1. Sucrose preference test [41] Before starting CUMS, all rats were given 1% sucrose water for 24 h. Then, both sucrose water and tap water were accessible to the rats for another 24 h. After receiving CUMS, animals

Please cite this article in press as: Qiao H, et al. Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.08.040

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Fig. 1. Experimental design. Asterisks ‘*’ show the time of performing experiments or sample collections after the onset of chronic unpredictable mild stress (CUMS).

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were subjected to the sucrose preference test. Rats were deprived of water and food for 23 h, and then given both sucrose water and tap water for 1 h. Sucrose and water consumption (100 ml) was measured and the sucrose preference was calculated as the sucrose preference (%) = sucrose consumption/(sucrose consumption + water consumption). 2.3.2. Open field test [42] The open field test was performed to measure spatial exploration behavior. Briefly, the apparatus consisting of a black square cage 60 cm × 60 cm × 40 cm and was divided into 5 × 5 equal small squares on the floor. A single rat was placed in the center of the cage, and then locomotion was recorded for 5 min by counting the total visit times of small squares using Video Mot2 (TSE, Germany). The cage was completely cleaned with 90% alcohol after each test. 2.3.3. Elevated plus maze test The elevated plus maze test is an anxiety paradigm based on the natural aversion of rats to a novel environment represented by the open and elevated spaces [43]. Rats were placed individually into the center of the maze facing an open arm and allowed to explore the maze freely for a 5 min testing period. The maze was thoroughly cleaned with 90% alcohol after each trial [44]. Time spent in open and closed arms was collected respectively using Video Mot2 (TSE, German).

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2.3.4. Tail suspension test [45] The tail suspension test is similar to the forced swim test, which measures “behavioral despair” (i.e. rats stop struggling in the face of an inescapable stressor). Each rat was suspended individually by its tail using adhesive laboratory tape to a flat metal bar connected to a strain gauge within a tail suspension chamber. The duration of the test was 6 min. Data acquisition and analysis was performed automatically, using Tail Suspension Monitor (TSE, German).

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2.4. Electrophysiology

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Electrophysiological recordings were performed 48 h after the behavioral test. After the animals were anesthetized with 20% urethane (1 g/kg, ip), they were placed in a stereotaxic frame (DM SYSTEM, Narishige, Japan) for surgery. A small hole was drilled in the skull with a dental drill at the site of the recording and stimulating electrodes. A bipolar stimulating electrode was placed in the Schaffer collateral pathway (3.0 mm posterior to bregma, 3.37 mm right to midline). The recording electrode was positioned in the stratum radiatum area of CA1 (3.45 mm posterior to bregma, 2.2 mm right to midline) [42,46]. The optimal depth of the electrode was determined by electrophysiological criteria (2.2–2.4 mm). At the end of recording, Pontamine Sky Blue was injected to mark the recorded site, and the brain was finally removed and sliced to verify the electrode positions (Fig. 3A). Input–output curves for the field excitatory postsynaptic potentials (fEPSPs) slopes were generated in order to evaluate the basal synaptic strength at the CA3-CA1 synapses. After selecting the best stimulation site and stabilizing the synaptic responses for 30 min, an input–output (I/O) curve was first determined for each group using measurements of fEPSPs slope in response to a series of stimulation intensities from

10 to 80 V. For quantification of the I/O relationship, fEPSP slopes were normalized for each animal by setting the largest slop value to 1.0 [47]. For LTP experiments [46], the baseline was recorded for 20 min (60% of the maximum response we tested above), and then highfrequency stimulation (HFS protocol consisting of 3 bursts of 100 Hz, 1 s pulses at 20 s intervals) was delivered to induce LTP. The fEPSPs were recorded for 80 min (Multiclamp 700B, Digidata 1440A; Axon Instruments, America). Initial analysis of the data was performed in Clampfit 10.0 (Molecular Devices, Sunnyvale, CA, USA). The slopes of evoked fEPSPs were normalized and expressed as a percentage of the average value measured during the last 20 min of baseline (n = 8). 2.5. Western blot Twenty-four hours after the behavior test, the hippocampi were collected (n = 8) and Western blot was performed as described [26]. Protein samples (60 ␮g/lane) were separated using SDSPAGE and transferred to PVDF membrane. The membranes were incubated with mouse anti-BDNF (1:5000, B9436, Sigma) and rabbit anti-Kalirin-7 (1:1000) overnight at 4 ◦ C [26] after blocking, and primary antibodies were recognized with horseradish peroxidase-conjugated goat anti-mouse IgG (1:7500, Bioss) and goat anti-rabbit IgG (1:5000, Bioss) for 1 h at 20 ◦ C. To normalize protein content, blots were stripped in stripping buffer and then probed with an anti-GAPDH antibody (1:1000). The densitometric values of the target protein of each group were normalized to GAPDH [48], and then expressed as a percentage of control group values. 2.6. Golgi staining After behavioral tests, animals (n = 8) were deeply anesthetized with sodium pentobarbital and perfused with 0.1 M phosphate buffer solution (PBS, pH 7.4) followed by 4% paraformaldehyde in 0.1 M PBS [24]. Golgi staining was performed as described [26]. For dendritic spine counts, at least five CA1 pyramidal neurons from each rat were chosen based on the following characteristics: (1) the cells were in the dorsal CA1 and CA3 region of hippocampus; (2) the neurons had a pyramidal morphology that grossly appeared to be well-filled and evenly impregnated; (3) the apical dendritic shafts emanated from the soma; and (4) no morphological changes resulting from the Golgi–Cox staining. Spine quantification was performed by an experimenter blind to the experimental groups. Spines were counted manually on randomly selected second-order segments from the apical dendrites. Approximately 2–3 segments were counted per slide and at least 6 slides were used from each rat [49]. 2.7. Statistical analysis Statistical analyses were carried out using SPSS 16.0 and results were reported as mean ± SD except the I/O curve as mean ± SEM. Comparisons between experimental and control groups were performed by one way ANOVA followed by Fisher’s LSD post hoc test when appropriate and repeated measures ANOVA for

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between-group comparisons on I/O curve and LTP. Significant group difference was set as p < 0.05. A single value of the average spine density from each rat was used as an independent sample for the analysis. 3. Results 3.1. The behavioral changes during CUMS

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Decreased body weight gain, sucrose preference, altered locomotor activity, and increased duration of immobility are typical phenotypes of depression after CUMS [40,42]. Our data revealed that in comparison with controls, the three-week group of CUMS rats showed typical depressive-like behaviors, including lower sucrose preference (71.46 ± 2.14% in the three-week CUMS group and 87.82 ± 6.88% in control, p < 0.05) (Fig. 2A), lower locomotion activity (171.8 ± 29.11 in the three-week CUMS group and 319.1 ± 30.32 in control, p < 0.01) (Fig. 2B), and longer time spent in the closed arm (91.86 ± 7.38 s in the three-week CUMS group and 59.94 ± 4.78 s in control, p < 0.01) (Fig. 2C) and immobility time (145.28 ± 14.11 s in the three-week CUMS group and 114.33 ± 9.23 s in control, p < 0.01) (Fig. 2D). Some behavior alterations occurred in the two-week CUMS group, such as locomotor activity (167.3 ± 30.37 in the two-week CUMS group and 319.1 ± 30.32 in control, p < 0.01) (Fig. 2B) and the time spent in the closed arm in the elevated plus maze test (89.19 ± 8.57 s in the twoweek CUMS group and 59.94 ± 4.78 s in control, p < 0.01) (Fig. 2C). However, the one-week CUMS group did not show any differences in the depression-like behaviors in comparison with control (Fig. 2), suggesting the stressed rats did not develop the depressive-like behaviors in the early days of CUMS.

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3.2. Functional alterations at hippocampal CA3-CA1 synapses

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Several studies reported that chronic stress impaired LTP induction in the hippocampal CA1 region [4,50–53]. Does this impairment occur only in the end of chronic stress (3–8 weeks) [42,54,55]? Recent studies show that acute and chronic stresses often exert opposite effects on neuroplasticity [37,56–59]. Therefore, different neuroplasticity may be observed at different time points during three-week CUMS. To examine this hypothesis, functional plasticity of CA3-CA1 synapses was investigated one, two and three weeks after CUMS in vivo (Fig. 3). As shown in Fig. 3B, the I/O relationships of the slope of fEPSP exhibited a significant rightward shift in the two-week (F(1,14) = 48.75, p < 0.01) and three-week CUMS groups (F(1,14) = 78.25, p < 0.01) compared with no-stress control, suggesting that our CUMS protocol decreased basal synaptic transmission. Stimulation of Schaffer collaterals evoked a basal fEPSP in the CA1 region and HFS induced LTP, which was maintained for at least 1 h. An example of the fEPSP at baseline and tetanized conditions of the no-stress control, the two-week CUMS and the three-week CUMS groups were presented in Fig. 3A. The time course of fEPSP slopes normalized to the 20 min baseline period is shown in Fig. 3D. The fEPSP slopes increased immediately after the HFS and more or less stabilized to a level above the baseline. A significant LTP impairment was observed in the three-week group compared with the control (p < 0.05, Fig. 3C). While the normalized fEPSP slopes after HFS in the two-week CUMS group were higher than that in other three groups (Fig. 3D). The average fEPSP slopes were increased from 198.68 ± 15.22% of baseline in control (n = 11) to 231.89 ± 16.74% of baseline in the two-week group (n = 16) (p < 0.01, Fig. 3C). Lower basal synaptic transmission (rightward shifted I/O curve) (Fig. 3B) may be associated with the increased fEPSP slopes in the

two-week CUMS group. In Fig. 3A, we found that the original traces of both baseline (black) and LTP (red) in the two-week CUMS group were lower than those of no-stress control, respectively, and the baseline was significantly reduced than LTP. But in Fig. 3C and D, we normalized the baseline of each group to 100% to generate the figures, which resulted in a higher ratio of LTP/baseline in the two-week CUMS group compared with no-stress control (Fig. 3C and D). To confirm this enhanced LTP induction induced by CUMS in the two-week group, we repeated this LTP experiment with the same CUMS and LTP protocols in an independent study. In agreement with early study, the average fEPSP slopes after HFS was increased from 152.65 ± 8.75% of baseline (control, n = 3) to 209.39 ± 17.01% of baseline (two-week group, n = 8) (p < 0.01), accompanied by a rightward shift of I/O curve. The decreased basal synaptic transmission may contribute to enhanced LTP induction, and the enhancement of LTP actually is a phenomenon of metaplasticity, implying that the synapse’s previous history of activity determines its current plasticity [60]. According to these finding, we hypothesized that the expressions of Kalirin-7 and BDNF, playing a key role in LTP induction, were altered by CUMS. The next study was designed to test this hypothesis.

3.3. The expression of BDNF and Kalirin-7 The interactions of BDNF or Kalirin-7 with NMDA receptors and the GluR1 subunit of AMPA receptors in the postsynaptic side of excitatory synapses have been documented [4,21,27,61]. These interactions may be involved in the mechanism of altered synaptic transmission in the two-week CMUS group. Using Western blotting, we detected decreased BDNF levels in the hippocampus in the three-week CUMS group (83.31 ± 4.58% of control, p < 0.05) (Fig. 4A and B) and the two-week CUMS group (46.53 ± 3.19% of control, p < 0.01) (Fig. 4A and B). Kalirin-7 plays an essential role in the formation of dendritic spines and synaptic function in hippocampal CA1 pyramidal neurons [22,26]. The significantly decreased expression of Kalirin-7 in the hippocampus was only observed in the three-week CUMS group (73.31 ± 4.38%, p < 0.01) but not the twoweek CUMS group compared with no-stress control group (Fig. 4C and D). Decreased expression of Kalirin-7 raised a possibility that CUMS exposure decreased spine density in CA1 pyramidal neurons. To determine this possibility, Golgi staining was used to analyze spine density in CA1 and CA3 pyramidal neurons during CUMS as described [26].

3.4. Dendritic spine density in CA1 and CA3 pyramidal neurons The number of apical dendritic spines in CA1 and CA3 pyramidal neurons was gradually decreased during three weeks of CUMS, and a significant decrease in spine density was only observed in the three-week CUMS group (CA1: 5.88 ± 2.06/10 ␮m; CA3: 5.94 ± 1.53/10 ␮m) (Fig. 5E–G, H–I) compared with no-stress control (CA1: 12.63 ± 1.98/10 ␮m; CA3: 12.43 ± 2.89/10 ␮m, p < 0.05) (Fig. 5A–D, H–I), in agreement with previous reports that chronic restraint stress, social isolation stress or exposure to stress hormone, corticosterone, by mimicking stress-mediated corticosterone secretion caused a decrease in spine density in CA1 pyramidal neurons [36,62]. These changes in spine density may contribute to the behavioral alterations after CUMS. A significant difference between no-stress control (CA1: 12.63 ± 1.98/10 ␮m; CA3: 12.43 ± 2.89/10 ␮m) and the other two CUMS groups was not detected (CA1: 11.18 ± 2.53/10 ␮m; CA3: 10.99 ± 3.16/10 ␮m, the one-week CUMS group and CA1: 9.70 ± 2.86/10 ␮m; CA3: 10.46 ± 1.75/10 ␮m, the two-week CUMS group) (Fig. 5H–I).

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Fig. 2. Behavioral tests were performed on days 0, 7, 14, and 21 after the onset of chronic unpredictable mild stress (CUMS), day 0 is no-stress control animals. (A) Sucrose preference test (F(3,28) = 6.13, p < 0.05). (B) Locomotor activity in open field test (OFT), “n” represents the total visit times of small squares. (F(3,28) = 16.99, p < 0.01). (C) Time spent in closed arms in elevated plus maze (F(3,28) = 11.84, p < 0.01). (D) Immobility time in tail suspension test (F(3,28) = 5.14, p < 0.01). One-way ANOVA followed by Fisher’s LSD post hoc test. *p < 0.05, **p < 0.01 vs. no-stress control.

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4. Discussion Animal models are key tools for studying human diseases. CUMS has been used as a valuable model of depression, because it induces behaviors that resemble certain core futures of human major depression [42,63,64]. Many studies exploring the effects of various antidepressants have utilized this model [29,65,66]. However, previous studies of depression using this model usually focused mainly on the final result at the end of CUMS exposure instead of the time course of changes during CUMS. In order to understand the progressive alterations of neuronal plasticity and the development of depressive-like behaviors during CUMS, and elucidate the possible mechanisms of CUMS-mediated spine/synaptic plasticity, we analyzed the time course of alterations of depressive-like behaviors, basal synaptic transmission, LTP induction, dendritic spine density in the CA1 and CA3 pyramidal neurons, and the expression of Kalirin-7 and BDNF in the hippocampus during CUMS (Figs. 3–5). 4.1. Time course of changes in depressive-like behaviors, LTP induction, dendrite spine density and gene expression during CUMS Our behavioral tests showed that the protocol of three-week CUMS successfully induced depressive-like behaviors in rats, including anhedonia (i.e. drinking less sweet solution), psychomotor retardation (i.e. decreased locomotor activity), and behavioral despair (i.e. a decreased struggle in the face of an inescapable

stressor) (Fig. 2), in agreement with previous reports [42,64]. In vivo recording demonstrated decreased basal synaptic transmission shown by a rightward shift of I/O curves, and an impaired LTP at CA3-CA1 synapses in the three-week CUMS group compared with no-stress control group (Fig. 3). Lower expression of both BDNF and Kalirin-7, and reduced dendritic spine density compared with no-stress control may contribute to decreased basal synaptic transmission and impaired LTP in the three-week CUMS group (Figs. 4 and 5). Simultaneous decrease in Kalirin-7 levels and the number of dendritic spines in the three-week CUMS group suggests a key role of Kalirin-7 in regulating the dendritic spine density in CA1 and CA3 pyramidal neurons during CUMS (Fig. 5). These results demonstrated that the functional and structural changes in CA1 pyramidal neurons and the decreased expressions of BDNF and Kalirin-7 after three-week CUMS are closely related with CUMSinduced depressive-like behaviors. In behavioral tests, some depressive-like behaviors including decreased locomotor activity and increased time spend in closed arms in elevated plus maze test, occurred in the middle phase of CUMS (two-week) (Fig. 2). At the same time, a weaker input–output relationship was also detected in the two-week CUMS group without a significant reduction of dendritic spine density in the CA1 pyramidal neurons compared with no-stress control group, and LTP induction at the CA3-CA1 synapses in this group was facilitated temporarily (Fig. 3). In the one-week CUMS group, no typical depressive-like behaviors were observed. These results showed that three weeks are required for developing depressivelike behaviors during CUMS.

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Q4 Fig. 3. Electrophysiological in vivo recordings of hippocampal CA3-CA1 synaptic transmission during different stages of chronic unpredictable mild stress (CUMS). (A) The recorded position; representative postsynaptic potential evoked in the stratum radiatum of the CA1 area by stimulating the Schaffer collaterals pathway in no-stress control, and in the two- and three-week CUMS animals before (black) and 60 min after high-frequency stimulation (HFS) (red). (B) Input–output activity of the hippocampal CA3-CA1 synapses. Data were reported as means ± SEM and analyzed by repeated-measure ANOVA (F(3,28) = 127.341, p < 0.01). (C) Bar graphs show increases in fEPSP slope in the four groups. Data were analyzed by ANOVA followed by Fisher’s LSD post hoc test (F(3,39) = 82.9, p < 0.01). *p < 0.05, **p < 0.01, day 0, no-stress control group: n = 11; day 7 CUMS group: n = 8; day 14 CUMS group: n = 16; day 21 CUMS group: n = 8. (D) fEPSP slope was normalized to baseline and plotted against time. The arrows represent the application of HFS (8× 100 Hz for 6 s repeated 30 times). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

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4.2. The regulation of LTP induction, dendritic spines, and expression of Kalirin-7/BDNF by stress To our knowledge, current study was the first to use in vivo recording to study the effect of CUMS on LTP induction at rat hippocampal CA3-CA1 synapses. Our results showed that threeweek CUMS exposure decreased basal synaptic transmission and impaired induction of LTP at the CA3-CA1 synapses recorded in vivo. It is generally thought that chronic stress induces inhibition of LTP and facilitates long-term depression (LTD) in the hippocampal CA1 region [67–69]. Therefore, a bias toward LTD in depression and a reduced capacity to induce LTP were thought to represent a state of lowered metaplasticity [4]. Some studies showed three-week CUMS impaired [50], or facilitated [59], or had no effect on LTP induction [70] at the CA3-CA1 synapses when recorded in vitro slices. These discrepancies in CUMS-mediated LTP induction could result from different LTP induction protocols, different recording methods, different CUMS protocols, and different age of animals. In the two-week CUMS group, basal synaptic transmission was also decreased, whereas the induction of LTP was facilitated, and BDNF expression in this two-week CUMS group was decreased at the same time. A previous study showed that LTP induction at CA3-CA1 synapses was enhanced via a weak stimulation and was impaired via a strong stimulation in vitro slices of animals received

three-week CUMS compared with no-stress animals [59], and LTP in the dentate gyrus was enhanced after 14 days of chronic restraint stress [37]. These results together with our findings showed that LTP was impaired in different forms during CUMS. In our current study, enhanced LTP and decreased BDNF expression in the twoweek CUMS group are not in line with some reports that show the effect of BDNF on LTP induction in the hippocampal neurons [71,72]. How to understand enhanced LTP induction and decreased expression of BDNF here? Synaptic release of BDNF induced by HFS plays a key role in HFS-induced LTP induction in hippocampal neurons [73–75]. Our Western blot analysis detected a decrease of total BDNF in the hippocampus. Therefore, it is possible that the HFS induced-release of BDNF from dendrites or axon may be enhanced by two-week CUMS, and stress may make the neurons more sensitive to HFS at the two-week time point compared with the neurons of no-stress control animals, which may contribute to enhanced LTP induction. A previous report showed that CUMS reduced BDNF in the dentate gyrus, but did not affect BDNF expression in the CA1-CA3 regions [76]. Several other studies showed no changes in the levels of BDNF mRNA and protein [77,78] or an increase in BDNF mRNA levels in the hippocampus by CUMS [79]. It is well documented that chronic stress causes a decrease in spine density in CA3 dendrites and CA3 dendrite atrophy [17,20,38,80,81]. Chronic restraint

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synapses and interacts with many postsynaptic proteins including NR2B, PSD95 and GluR1 [27,61]. Kalirin is also a down-stream signal of BDNF. Exogenous BDNF stimulates neurite outgrowth and branching in hippocampal neurons, and it is unable to do so in neurons in which expression of kalirin has been reduced (Yan Y, Mains RE and Eipper BA, Neuroscience Meeting poster, 417.09/EI, Society for Neuroscience, San Diego, CA, 2013). Kal-7KO mice show decreased spine density in CA1 pyramidal neurons and are deficient in hippocampal LTP [26,86]. Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity [86]. These results showed that BDNF or NMDA receptor-mediated synaptic plasticity may be through Kalirin-7. In addition, BDNF is also associated with presynaptic modulation of glutamate release in synaptosomes [87,88]. BDNF enhances synaptic transmission through regulating presynaptic vesicle cycling and mitochondria at presynaptic sites [89,90]. Decreased levels of BDNF may predominantly affect basal synaptic transmission via a presynaptic pathway, while Kalirin-7, a key postsynaptic protein, that is required for LTP induction and synaptic plasticity, was not altered by CUMS at the two-week time point. Under this special circumstance, a possible increase in the sensitivity of the CA3-CA1 synapses to HFS induced by CUMS may be associated with enhanced LTP in the two-week CUMS group. One of our next directions is to determine why LTP induction was enhanced in the two-week CUMS animals.

4.3. The role of Kalirin-7 in spine/synaptic plasticity during CUMS

Fig. 4. Expressions of BDNF and Kalirin-7 in the hippocampus at different stages after chronic unpredictable mild stress (CUMS). (A) Microphotographs of Western blot analysis show BDNF expressions in the four groups: 0 (no-stress control), one-, two-, and three-week CUMS groups. (B) Bar graphs show the levels of BDNF expression during CUMS (n = 8). (C) Microphotographs of Western blot analysis show Kalirin-7 expression in the four groups. (D) Bar graphs show the levels of Kalirin-7 in the four groups during CUMS. *p < 0.05, **p < 0.01.

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stress caused a decrease in dendritic spine density in mouse CA1 pyramidal neurons, but did not alter BDNF protein in the hippocampus [36]. These finding together with our results suggested that decreased expression of BDNF is not a necessary condition for stress-mediated synaptic plasticity and dendritic remodeling. Enhanced LTP and decreased basal synaptic transmission in the two-week CUMS animals suggest the neurons were more sensitive to HFS stimulation, a temporarily protective mechanism of the neurons to offset the destructive effects of CUMS on the hippocampus. The regulation of the synaptic transmission by BDNF is through NMDA receptors, particularly the NR2B subunit [82–85]. Kalirin7 is exclusively localized to the postsynaptic side of excitatory

Chronic stress causes the loss of dendritic spines and/or the retraction of apical dendrites of the hippocampal CA1 [7,17,36] and CA3 pyramidal neurons [17,20,80,81]. Kalirin-7 plays an essential role in spine/synapse formation in hippocampal pyramidal neurons in vitro and in vivo [22,25,27]. Hippocampal CA1 pyramidal neurons of Kalirin-7 knockout mice show a decrease in spine density and a deficiency in LTP induction [26]. In our current study, the decrease in both spine density in the CA1/CA3 pyramidal neurons and Kalirin-7 expression in the hippocampus was only found in the three-week CUMS group, a time point at which overall depressivelike behaviors were observed (Figs. 4–5). These findings suggest that Kalirin-7 plays a key role in the CUMS-induced loss of dendritic spines and decreased induction in LTP in the hippocampus. However, the pathways through which Kalirin-7 was decreased by CUMS are not clear, which is a focus of our future directions. In the three-week CUMS group, a reduction in dendritic spine density may lead to a decrease in total synaptic surface area on postsynaptic dendrites which may adversely affect the availability of synaptic inputs, thereby reducing the neuron’s ability to generate normal LTP. Taken together, our findings strongly support our hypothesis that the changes induced by CUMS may represent a neuroadaptive consequence rather than a rapid modification of structure due to stress exposure. During three-week CUMS, altered synaptic plasticity occurred in the two-week CUMS animals in which decreased BDNF levels may contribute to the decreased basal synaptic transmission at the hippocampal CA3-CA1 synapses. CUMS may cause an increase in the sensitivity of the CA3-CA1 synapses to HFS, which together with decreased basal synaptic transmission may be associated with enhanced LTP in the twoweek CUMS group. In the three-week CUMS group, the lower expression of Kalirin-7 and a decrease in dendritic spine density may be crucial factors responsible for the functional change of the CA3-CA1 synaptic transmission and the depressive-like behaviors. Our results support our hypothesis that functional adaptation takes place during the development of CUMS-induced depression-like behaviors.

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Fig. 5. Dendritic spine density in hippocampal CA1 and CA3 pyramidal neurons after chronic unpredictable mild stress (CUMS). Representative microphotograph of Golgi staining shows the dendritic spines of CA1 pyramidal neurons from the no-stress control (A–D) and the three-week (E–G) CUMS group. High power images D and G are from the circled areas of C and F, respectively. Bar graphs (H–I) show the dendritic spine density of hippocampal CA1 (F(3,28) = 16.05, p < 0.01) and CA3 (F(3,28) = 33.46, p < 0.01) pyramidal neurons.**p < 0.01.

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Acknowledgements The work was supported by National Natural Science Foundation of China (81371512), NIH (DA032973), and Fundamental Research Fund for the Central Universities (GK201402028). Thanks to Dr. Eric Levine and Maegan Gross for their reading of the manuscript.

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Please cite this article in press as: Qiao H, et al. Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.08.040

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Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression.

Major depressive disorder is the most prevalent psychiatric condition, but the cellular and molecular mechanisms underlying this disorder are largely ...
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