Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long-term depression and behavioral flexibility
- Kyungmin Lee†1,
- Yuki Kobayashi†2,
- Hyunhyo Seo1,
- Ji-Hye Kwak1,
- Akira Masuda2,
- Chae-Seok Lim4,
- Hye-Ryeon Lee4,
- SukJae Joshua Kang5,
- Pojeong Park5,
- Su-Eon Sim5,
- Naomi Kogo2,
- Hiroaki Kawasaki3,
- Bong-Kiun Kaang4, 5 and
- Shigeyoshi Itohara2Email author
© Lee et al. 2015
Received: 17 April 2015
Accepted: 15 June 2015
Published: 24 June 2015
Guanine nucleotide exchange factors (GEFs) activate small GTPases that are involved in several cellular functions. cAMP-guanine nucleotide exchange factor II (cAMP-GEF II) acts as a target for cAMP independently of protein kinase A (PKA) and functions as a GEF for Rap1 and Rap2. Although cAMP-GEF II is expressed abundantly in several brain areas including the cortex, striatum, and hippocampus, its specific function and possible role in hippocampal synaptic plasticity and cognitive processes remain elusive. Here, we investigated how cAMP-GEF II affects synaptic function and animal behavior using cAMP-GEF II knockout mice.
We found that deletion of cAMP-GEF II induced moderate decrease in long-term potentiation, although this decrease was not statistically significant. On the other hand, it produced a significant and clear impairment in NMDA receptor-dependent long-term depression at the Schaffer collateral-CA1 synapses of hippocampus, while microscopic morphology, basal synaptic transmission, and depotentiation were normal. Behavioral testing using the Morris water maze and automated IntelliCage system showed that cAMP-GEF II deficient mice had moderately reduced behavioral flexibility in spatial learning and memory.
We concluded that cAMP-GEF II plays a key role in hippocampal functions including behavioral flexibility in reversal learning and in mechanisms underlying induction of long-term depression.
The newly identified cAMP-binding proteins known as cAMP-guanine nucleotide exchange factors (cAMP-GEFs) have provided novel insights regarding the action of cAMP on intracellular signaling and cellular functions. cAMP-GEFs, which are directly activated by cAMP, are GEFs responsible for the activation of the Ras-related small GTPases Rap1 and Rap2 [1, 2]. Previous pharmacological studies have demonstrated that cAMP-GEFs play a role in increasing neurotransmitter release and inducing synaptic potentiation in cortical and hippocampal pyramidal neurons [3–5]. In addition to their presynaptic functions, pharmacological studies have also shown that cAMP-GEFs can control the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways through the activation of Rap proteins, and modulate synaptic plasticity via α-amino-3-hydroxy-5-methyl-4-isoxazloe propionic acid (AMPA) receptor trafficking in postsynaptic densities . cAMP-GEFs are subdivided in cAMP-GEF I (also known as RapGEF3 or Epac1) and II (also known as RapGEF4 or Epac2), and these two isoforms show differential expression in the brain. cAMP-GEF I is expressed broadly at low levels in the adult brain, whereas cAMP-GEF II is strongly expressed in the mature brain, with high levels in the cerebral cortex and CA3 and dentate gyrus of the hippocampus .
cAMP-GEF II has been implicated in various brain functions such as memory and sociability. In mice, knockdown of cAMP-GEF II reduced fear memory retrieval in contextual fear conditioning , and cAMP-GEF II deficiency impaired social and communication behavior . Furthermore, a recent work has shown that cAMP-GEF I/II double-null mice on a 129sv background presented deficits in hippocampal spatial learning, with impairment of long-term potentiation (LTP), but not long-term depression (LTD) . However, the specific role of cAMP-GEF II in hippocampal synaptic plasticity and cognitive functions as well as their related mechanisms remain elusive. In the present study, we investigated whether cAMP-GEF II contributes to the modulation of hippocampal Schaffer collateral (SC)-CA1 synapses, and how cAMP-GEF II is involved in hippocampus-dependent cognitive functions, using a cAMP-GEF II knockout mouse generated on a C57BL/6 J background.
Generation of cAMP-GEF II −/− mice and cAMP-GEF II protein expression in the brain
Long-term potentiation is moderately decreased in cAMP-GEF II −/− mice
Presynaptic functions are intact in cAMP-GEF II −/− mice
Considering previous reports showing that cAMP-GEF activation by 8-(4-chlorophenylthio)-2’-O-methyl-cAMP (8-CPT-cAMP), a selective cAMP-GEFs agonist, induced enhancement of neurotransmitter release in cultured hippocampal neurons , a deficiency in cAMP-GEF II can change the neurotransmitter release at presynaptic terminals, leading to changes in synaptic plasticity. To further explore the presynaptic involvement of cAMP-GEF II in hippocampal synapses, we monitored two forms of presynaptic short-term plasticity: paired-pulse facilitation (PPF) and post-tetanic potentiation (PTP). PPF was induced by stimulation of a pair of SC-CA1 synapses at short intervals (20, 50, 100, or 200 ms), which is known to be sensitive to presynaptic release probability . PTP was analyzed using a protocol composed of a single train of tetanic stimulation (100 Hz for 1 s) in the presence of D(−)-2-amino-5-phosphonovaleric acid (D-APV; 25 μΜ) to block NMDA receptor-dependent postsynaptic modifications. Both PPF and PTP were indistinguishable between wild-type and cAMP-GEF II −/− mice (Fig. 2c, d, respectively), suggesting that hippocampal presynaptic functions associated with short-term plasticity were unchanged in cAMP-GEF II −/− mice.
NMDA receptor-dependent long-term depression (NMDAR-LTD) is impaired in cAMP-GEF II −/− mice
Behavioral flexibility is altered in cAMP-GEF II −/− mice
In the present study, we examined the role of cAMP-GEF II in synaptic plasticity and hippocampus-dependent cognitive function using genetic approaches. We found that function of cAMP-GEF II is more closely related to NMDAR-LTD than to LTP or depotentiation, and that the alteration of synaptic responses and plasticity was associated with postsynaptic changes in the SC-CA1 pathway of the hippocampus. In addition, the impairment in NMDAR-LTD was accompanied by a reduction of behavioral flexibility in cAMP-GEF II −/− mice.
cAMP-GEF II in presynaptic axon terminals and postsynaptic densities
Modulation of presynaptic transmission and remodeling of postsynaptic spines are known to play a critical role in synaptic plasticity of brain circuits and in cognitive functions such as memory formation [19, 20]. In both pre- and postsynaptic processes, secondary messengers such as cAMP are key components regulating synaptic strength . Previous studies on the effect of cAMP on synaptic plasticity have shown that PKA activation by cAMP is an essential step . However, we cannot rule out the role of other cAMP-dependent (but PKA-independent) mechanisms such as the one involving cAMP-GEFs in synaptic function. Previous pharmacological studies using the cAMP-GEFs agonist 8-CPT-cAMP in Drosophila , exciter nerve axon of crayfish neuromuscular junction , calyx of Held of rat , and cultured hippocampal neurons , demonstrated that cAMP facilitates presynaptic transmission by increasing the number of neurotransmitter-releasing vesicles through activation of the PKA-independent cAMP-GEFs pathway in axon terminals. However, in the present study, and in agreement with a previous report by Yang and colleagues using Epac2 null mice , we could not find any evidence for a role of cAMP-GEF II in presynaptic transmission in the hippocampal SC-CA1 synapses of cAMP-GEF II −/− mice. Therefore, we assume that discrepancies may arise from differences between animal species or type of neurons used for experiments, for instance exciter nerve axon of cray fish  or calyx of Held of rat  versus hippocampal CA1 pyramidal neuron in mice used in this study. It should be also noted that 8-CPT-cAMP activates both cAMP-GEF I and II. In any case, our data suggest that the impairment in hippocampal synaptic plasticity observed in cAMP-GEF II −/− mice was induced by postsynaptic alterations, rather than presynaptic changes. Furthermore, western blot analysis using synaptic membrane fractions containing PSDs also supported the postsynaptic function of cAMP-GEF II. Supporting this, a proteomic study using mass spectrometry (LC-MS/MS) detected cAMP-GEF II protein in forebrain PSDs , and cAMP-GEF II protein colocalized with the postsynaptic marker PSD-95, suggesting a functional role for cAMP-GEF II in dendritic spines . All these data strongly support our findings on the role of cAMP-GEF II in postsynaptic function.
cAMP-GEF II and long-term depression
It has been previously shown that the small GTPase Rap1 mediates NMDA receptor-dependent AMPA receptor internalization during LTD . Moreover, Ster and colleagues  reported that in mouse hippocampal slices, cAMP-GEFs activation by 8-CPT-cAMP induced LTD with a postsynaptic mechanism dependent on the interaction of AMPA receptor and PDZ proteins, activation of small GTPase Rap1-p38 MAPK signaling, and intracellular Ca2+ stores. In agreement with this previous report, we show in our study that cAMP-GEF II is highly associated with LTD induction.
However, in contrast to the lack of LTD and behavioral flexibility shown in cAMP-GEF II −/− mice in our study, a recent work has shown that cAMP-GEF I/II double-null mice on a 129Sv background presented impairment of LTP, but not LTD, with deficits in hippocampal spatial learning . In addition, cAMP-GEF II specific knockout mice showed normal hippocampal synaptic function and memory . The discrepancies between the data of Yang and colleagues  and ours, in both synaptic plasticity and behavioral testing, could be related to differences in the genetic background mice strains used. We used C57BL/6J mice, while Yang and colleagues  used 129Sv mice. Although inbred mouse strains are a powerful tool for a better understanding of gene function, brain region- and strain-specific variations in gene expression may yield differences in neural functions or neurobehavioral phenotypes across mouse strains [28, 29]. Indeed, several mouse genetic studies performed to assess mechanisms underlying neurobehavioral differences, detected that many genes were differentially expressed between C57BL/6 and 129Sv mouse strains [30, 31], and defined C57BL/6 and 129Sv mouse strains as different based on microarray gene expression profiling . Although a differential expression of cAMP-GEF I or II between these two strains has not been reported, many genes related to signaling pathways such as Ras-GTPase activating protein and Ras-like protein expressed in neurons presented clear differences in gene expression in nervous tissue [30, 31]. Therefore, we cannot rule out the effect of strain differences in gene expression on neural features and behavioral phenotypes. Alternatively or additionally, allele differences may in part account for these discrepancies. For instance, there is a general concern on cis-effects of a selection marker gene cassette near the targeted locus for the phenotypes of knockout or knockin mice [33–35].
cAMP-GEF II and behavioral flexibility
A large body of evidence has demonstrated that hippocampal synaptic depression plays an important role in memory processes [16, 36–38] and behavioral flexibility [17, 18]. In our study, we found that mice lacking cAMP-GEF II had a mild reduction in behavioral flexibility in the Morris water maze and a place preference learning task using the IntelliCage test. These results are consistent with impairment of hippocampal LTD in cAMP-GEF II −/− mice, although we cannot simply conclude that the behavioral results were a consequence of LTD impairment. In fact, cAMP-GEF II seems to have various roles in hippocampal-dependent memory with different downstream signaling pathways. Ostroveanu and colleagues  reported that an intra-hippocampal injection of 8-CPT-cAMP enhanced memory retrieval in the contextual fear conditioning via the Rap1-p42/p44 MAPK (ERK 1/2) signaling pathway, while memory acquisition was not affected. These results indicate that change in cAMP-GEF II activity is related to a variety of synaptic processes and cognitive functions, including behavioral flexibility and memory retrieval with distinct signaling pathways.
In our study, we verified a specific role of cAMP-GEF II in NMDAR-LTD induction and behavioral flexibility in hippocampal-dependent reversal learning, using a genetic deletion approach.
Generation of cAMP-GEF II−/− mice
The cAMP-GEFII floxed (with PGK-neo) allele was generated inserting a loxP into the 0.5 kb upstream of exon 3 and a FRT-pgk-neo-FRT-loxP cassette into the 0.5 kb downstream of exon 3. This line was generated using MS12 ES cell lines derived from the C57BL/6 strain , and maintained in a C57BL/6J genetic background. The cAMP-GEF II knockout (KO, cAMP-GEF II −/− ) allele was generated by inducing Cre-mediated recombination in the germline of cAMP-GEFII floxed mice.
All experiments were performed in accordance with RIKEN (Japan), Kyungpook National University (Korea), Seoul National University (Korea) regulations to minimize pain and discomfort to animals. All animal protocols were also in accordance with the guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health (NIH, USA).
PCR for genotyping
PCR primer pairs (Fig. 1a) for genotyping were as follows: P1, 5′-GTGTTACTCTAGAAACGAC-3′/ P2, 5′-TGTTTCGCCAAGGGGATATTG-3′/P3, 5′-CTGGTGCTCACACCTCGTAC-3′ (630- and 250-bp bands for wild-type and cAMP-GEF II −/− alleles, respectively).
Western blot analysis
Western blots were performed as previously reported [40, 41] with some modifications. In brief, cortex tissues were dissected out immediately after cervical dislocation. Tissues were homogenized on ice in 10-volume buffer A (5 mM HEPES, pH 7.4 containing 0.32 M sucrose) containing a protease inhibitor (Roche, cat# 04693159001) and PhosSTOP (Roche, cat# 04906845001) using a Teflon homogenizer. Samples were centrifuged at 1,400 × g for 5 min at 4 °C, and the resulting supernatants (S1) were further centrifuged at 14,200 × g for 20 min at 4 °C. Pellets (P2, crude membrane fraction) were suspended and lysed in 6 mM Tris buffer (pH 8.0, containing 0.5 % Triton X-100) on ice for 30 min. The SPM was fractionated using a layered sucrose gradient (0.8 M, 1.0 M, and 1.2 M sucrose in 5 mM HEPES) at 82,700 × g. The interface between 1.0 M and 1.2 M sucrose was retrieved, which included postsynaptic membranes and PSD proteins without presynaptic vesicles. Proteins of S1, P2, and SPM were separated using SDS-polyacrylamide gel electrophoresis, and electroblotted to polyvinylidene fluoride (PVDF) membranes. Membranes were immunoreacted with an anti-cAMP-GEF II polyclonal antibody (diluted 1:1000; Santa Cruz, cat# SC-25633), anti-Actin monoclonal antibody (1:10,000; Millipore, Cat# MAB1501), or anti-PSD95 polyclonal antibody (1:5000; Frontier Institute, Cat# PSD95-GP-Af248-2), and their appropriate species-specific HRP-conjugated secondary antibodies. Finally, immunoreactive bands were detected using Luminata Forte Western HRP Substrate (Millipore, cat# WBLUF0500).
Hippocampal slice preparation
Hippocampal slices were prepared from 3- to 5-week-old wild-type and cAMP-GEF II −/− mice (male and female). For depotentiation experiment 10- to 12-week-old animal was used to differentiate its effect with LTD. Animals were anesthetized with 2-bromo-2-chloro-1,1,1-trifluroethane and decapitated. Brains were then removed and placed in ice-cold artificial cerebrospinal fluid (ACSF), which was aerated with 95 % O2 and 5 % CO2. The ACSF contained the following: 124 mM NaCl, 2.5 mM KCl, 1 mM NaH2PO4, 25 mM NaHCO3, 10 mM glucose, 2 mM CaCl2, and 2 mM MgSO4. Transverse hippocampal slices (400-μm thick) were prepared using a manual tissue chopper (MK-MTC9100, Mickle Laboratory Engineering) and allowed to recover in ACSF at room temperature for 1 h. After preparation, slices were transferred to a recording chamber maintained at 28 °C, and then continuously perfused with aerated ASCF at a rate of 1.5 mL/min, before recordings were obtained.
Extracellular recordings were performed in the stratum radiatum of the CA1 area of hippocampal slices using a glass pipette filled with ACSF (1 MΩ) in order to measure the slope of evoked field excitatory postsynaptic potentials (fEPSPs). Schaffer collateral fibers were stimulated every 30 s using bipolar electrodes (MCE-100, Kopf Instruments). fEPSPs were amplified using an Axopatch 200B amplifier, and digitized with a Digidata 1322A A/D board for measurement, at a sampling rate of 10 kHz. Data were monitored and analyzed using the WinLTP program . Each experiment was conducted on separate slices, thus the n number represents the number of slices used for the experiment. For LTP and LTD, the stimulation intensity was adjusted to obtain fEPSP slopes of 45 % of the maximum. After a stable baseline period of over 30 min, high frequency stimulation (a single train of tetanus, 100 Hz for 1 s) or low frequency stimulation (1 Hz for 15 min) were applied, respectively. Depotentiation was induced using three trains of theta-burst stimulation (consisting of five pulses at 100 Hz, and repeated five times at 5 Hz) at 10 s of intertrain interval, followed 30 min later by low frequency stimulation (2 Hz, 10 min). For PTP, the NMDA receptor antagonist D-APV (25 μM, Tocris) was added to the ACSF during recording. PPF was induced by stimulation of a pair of afferent fibers at short intervals (20, 50, 100, or 200 ms), which is sensitive to presynaptic release probability .
Electrophysiology data analysis
Measurements were expressed as percentage of the averaged value calculated 10 min before LTP or LTD induction. Significant differences between groups were assessed using Student’s t-test of the last 10 min average values after LTP and last 5 min average values after LTD or depotentiation induction. Data are presented as mean ± SEM, and statistical significance was set at p < 0.05.
Generation of Antibody
KLH-coupled synthetic peptides (CQMSHRLEPRRP) corresponding to the C-terminus of cAMP-GEFII were used to raise a rabbit polyclonal antibody (BSI Research Resources Center).
Mice were fully anesthetized and a needle was inserted directly into the left ventricle. Animals were then perfused using 4 % paraformaldehyde pH 7.4 (0.5 mL/g of body weight) at a speed of 1 mL/min. Brains were removed, post-fixed in 4 % paraformaldehyde overnight at 4 °C, and cryoprotected in 0.1 M phosphate buffer (PB) containing 30 % sucrose. For immunohistochemistry of cAMP-GEF II, thin sections (5 μm thick) from paraffin-embedded samples were deparaffinized, rehydrated, and processed for heat-induced epitope retrieval. After blocking in 4 % normal goat serum for 1 h, tissue sections were reacted with a rabbit anti-cAMP-GEF II antibody (diluted 1:2000) at 4 °C overnight, and then incubated in biotinylated anti-rabbit IgG (1:200, Vector Laboratories, Burlingame, CA, USA) at room temperature for 2 h. After washing in phosphate buffered saline containing Triton X-100 (PBST), sections were incubated in avidin-biotin-peroxidase complex (1:250 dilution, ABC Elite; Vector Laboratories) at room temperature for 1 h. The horseradish peroxidase reaction was developed in 0.1 M Tris–HCl (pH 7.4) containing 0.05 % 3,3´-diaminobenzidine, and 0.01 % H2O2., and sections were dehydrated. Bright-field images were taken with a digital slide scanner (NanoZoomer; Hamamatsu Photonics). For immunofluorescence, tissue blocks were sectioned in the coronal plane (30 μm thick), and free-floating sections were post-fixed in 50 % ethanol for 10 min at room temperature. After blocking with 4 % normal goat serum, sections were permeabilized with 0.3 % Triton X-100 in phosphate buffered saline (PBS) for 3 h, and incubated with NeuN (1:1000 dilution, Millipore) antibody overnight at 4 °C. Immunolabeling was visualized using an anti-mouse secondary antibody conjugated to Alexa 488 (1:500, Invitrogen) at room temperature. Sections were then dehydrated, mounted on glass slides, and visualized using a confocal microscope (LSM700, Zeiss).
Novel location recognition test
Mice (6-month-old males; n = 10 WT, n = 12 KO) were habituated to an empty cage (21 x 42 x 21 cm) for 10 min per day for 3 days before starting the experiment. For identical objects (A and B), two identical plant pots were used. On day 4, object A was placed in the center of the cage and object B was placed next to object A (i.e., control session). Mice were free to explore for 5 min in the cage, and then they were moved to a homecage. Two hours later, location of object B was changed, and mice were free to explore for 5 min in the cage again (i.e., test session). The time spent touching an object was recorded from a camera mounted overhead, and was manually counted. The discrimination index calculation formula was as follows: discrimination index = (contact duration of object B)/(total contact duration of objects).
Morris water maze task
The Morris water maze test was performed according to the procedure described previously by Nishiyama and colleagues , with some modifications. The water pool used in the current experiment was 1.5 m in diameter and illuminated with 300 lux white fluorescent light at the maze-surface level. The pool temperature was kept at 25 ± 1 °C. The acrylic transparent platform (diameter 10 cm) was submerged 0.7 cm below the surface of water made opaque by adding nontoxic white paint. The location of the platform was fixed over a series of trials for each mouse. If the mouse located the platform within 90 s, the mouse was allowed to remain on it for 30 s. Mice that failed to find the platform within 90 s were manually guided to the platform and allowed to remain on it for 30 s. Mice were given four trials per day for 19 consecutive days in a spaced manner. The inter-trial intervals for individual mice were about 30–60 min. A different randomly selected starting point along the rim of the maze was used for each of the four trials. On day 15, the platform position was changed to the opposite side of the initial target quadrant, and mice relearned the new platform position. A probe trial and a reversal probe trial were performed on days 14 and 19, respectively, after the acquisition sessions. In the probe tests, the platform was removed from the tank, and each mouse was allowed to swim for 90 s. Movement of each mouse in the maze was recorded using a video camera and analyzed with NIH IMAGE WM 2.12 (O’Hara & Co.) software.
Place preference learning task with IntelliCage
The IntelliCage apparatus and software (NewBehavior AG) have been described previously [13, 14], and we performed the IntelliCage test as previously reported , with some modifications. Radiofrequency identification transponders (Planet ID GmbH) were implanted subcutaneously in the dorsocervical region. During all adaptation phases and tasks, mice were fed ad libitum. Adaptation phase was 3 weeks. During the first week, all doors were open; mice were free to access all four corners, which had water bottles (i.e., free adaptation). During the second week, all doors were closed but could be opened once per visit with a nose-poke for 5 sec (i.e., nose-poke adaptation). During the third week, mice were adapted to a fixed drinking schedule (i.e., drinking session adaptation) with doors opening in response to nose-pokes between the hours of 21:00–24:00 only. In the place preference task, water was available in only one of the four corners (i.e., correct corner) during the drinking session. This task was performed for 7 days, and the number of corner visits was counted for 3 h. Performance was quantified as the percentage of correct corner visits. In the reversal learning task, water was available only in the opposite corner (i.e., new correct corner) during the drinking session. This task was also performed for 7 days, and the number of corner visits was counted for 3 h.
Foot shock sensitivity test
Foot shock sensitivity was assessed by giving mice electrical shocks of increasing intensity, ranging from 0.05 mA to 1 mA, and monitoring their behavior (i.e., flinching, vocalization, and jump).
Statistical analysis for behavioral tests
Data were analyzed using a Two-way ANOVA, Two-way repeated measurements ANOVA (RM ANOVA), and Unpaired t-tests. Probability values (p) less than 0.05 were considered statistically significant.
K. Lee was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (grant# NRF-2013R1A1A3010216); and the National Honor Scientist Program (grant# NRF-2013R1A3A1072702). H. Seo was supported by a BK21 Plus grant funded by the Ministry of Education of Korea (grant# 21A20132212094). B.K.Kaang was supported by the National Honor Scientist Program. S. Itohara was supported in part by Takeda Pharmaceutical Co. Ltd., and FIRST program initiated by the Council for Science and Technology Policy of Japan. YK and SI wish to thank Atsuko Oba-Asaka for her technical help.
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