Cdk5/p35 functions as a crucial regulator of spatial learning and memory
© Mishiba et al.; licensee BioMed Central Ltd. 2014
Received: 14 July 2014
Accepted: 3 November 2014
Published: 18 November 2014
Cyclin-dependent kinase 5 (Cdk5), which is activated by binding to p35 or p39, is involved in synaptic plasticity and affects learning and memory formation. In Cdk5 knockout (KO) mice and p35 KO mice, brain development is severely impaired because neuronal migration is impaired and lamination is disrupted. To avoid these developmental confounders, we generated inducible CreER-p35 conditional (cKO) mice to study the role of Cdk5/p35 in higher brain function.
CreER-p35 cKO mice exhibited spatial learning and memory impairments and reduced anxiety-like behavior. These phenotypes resulted from a decrease in the dendritic spine density of CA1 pyramidal neurons and defective long-term depression induction in the hippocampus.
Taken together, our findings reveal that Cdk5/p35 regulates spatial learning and memory, implicating Cdk5/p35 as a therapeutic target in neurological disorders.
KeywordsSpatial learning Memory Kinase Synaptic plasticity Hippocampus
Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is abundant in neuronal cells and is activated by complexing with p35 or p39. Recent studies have demonstrated that Cdk5 is critically involved in synaptic plasticity, a cellular basis of memory formation , in addition to its function in neuronal development -. At presynaptic terminals, Cdk5 regulates neurotransmitter release via phosphorylation of presynaptic proteins such as synapsin I and N-type voltage-gated calcium channels ,. Alternatively, at postsynaptic dendritic spines, Cdk5 phosphorylates postsynaptic proteins such as postsynaptic density protein 95 (PSD-95) , NMDA receptor subunit NR2A , protein phosphatase inhibitor-1 , dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) , and tropomysin-related kinase B (TrkB) . Moreover, inducible Cdk5 conditional knockout (cKO) mice show enhanced synaptic plasticity and improved spatial learning and memory via an increase in synaptic NR2B subunits of NMDA receptors . More recently, it was shown that disrupting long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal CA1 of mice lacking Cdk5 results in the impairment of spatial learning and memory partly due to the collapse of cAMP signaling . These two results, however, are likely secondary consequences of the loss of Cdk5 function as a scaffold protein  and a regulator of other signaling pathways, respectively. Therefore, the original functions of Cdk5 in synaptic plasticity and in the phosphorylation of synaptic proteins remain to be elucidated.
We have previously demonstrated an impairment of spatial learning and memory, and hippocampal LTD induction in p35 knockout (KO) mice. However, p35KO mice exhibit reversed cortical lamination of cerebral cortex and mild disorganization of cellular alignment of CA1 pyramidal neurons and dentate gyrus . These histological abnormalities in the brain may confound these results . To further investigate the role of Cdk5/p35 in higher brain function without histological abnormalities, we generated inducible p35 conditional knockout (cKO) mice, in which p35 is deleted in all cells by breeding p35-flox mice with CreER-mice . We found that CreER-p35 cKO mice have defective spatial learning and memory, along with decreased anxiety-like behavior. We also showed reduced spine density of pyramidal neurons, reduced sensitivity to synaptic input, and impaired LTD induction in the hippocampal CA1. Biochemical analysis revealed no alteration of NR2B protein in the hippocampi of CreER-p35 cKO mice. These findings indicate that the kinase function of Cdk5/p35 is essential for normal synaptic function and spatial learning and memory.
Reduction of p35 protein in the brains of p35-flox; CreER mice by oral administration of tamoxifen
Normal locomotor activity and reduced anxiety-like behavior in CreER-p35 cKO mice
The anxiety-like behavior of CreER-p35 cKO mice was assessed with an elevated plus maze (Figure2B). The total distance traveled by CreER-p35 cKO mice was a little longer than that by control mice. The time CreER-p35 cKO mice spent in the closed arm was significantly shorter than that in control mice, while CreER-p35 cKO mice remained in the open arm somewhat longer than control mice. These results suggest that CreER-p35 cKO mice have reduced anxiety-like behavior.
Defective spatial learning and memory in CreER-p35 cKO mice
The platform was removed after the hidden platform task, and mice were allowed to swim freely in the probe test. The time spent in the target quadrant (where the platform had been formerly located) was significantly longer than the time spent in the other quadrants for control mice, while the time spent in the target quadrant was not different from the time spent in the other quadrants for CreER-p35 KO mice (Figure3B). The number of times that CreER-p35 cKO mice crossed the region where the platform used to be located was significantly less than that by control mice (Figure3C). CreER-p35 cKO mice swam almost as far and as fast as control mice (Figure3C). In the visible platform test, however, the total distance swam by CreER-p35 cKO mice was approximately equal to that by the control mice (Figure3D). These results suggest that spatial learning and memory are significantly impaired in CreER-p35 cKO mice.
Reduction in dendritic spine density in CreER-p35 cKO mice
Impaired synaptic properties in CreER-p35 cKO mice
To test whether loss of p35 affects synaptic plasticity, we next examined if there were any changes in hippocampal LTD in CreER-p35 cKO mice. LTD in adult mice was induced using low-frequency stimulation (LFS) combined with the application of the glutamate transporter inhibitor, tPDC . To determine if this form of LTD is NMDAR-dependent, LTD was induced in the presence of the NMDA blocker, D-AP5. We found that LTD was significantly blocked by D-AP5, indicating that LTD is largely NMDAR-dependent (Additional file 2: Figure S2). We found that LTD induction was significantly impaired in CreER-p35 cKO mice when compared with control (Figure5D; control, 82.1 ± 2.3%; p35 cKO, 98.2 ± 2.3%; unpaired t-test, p =0.0003). We next examined if LTP was affected in CreER-p35 cKO mice. Using 3 theta-burst stimulations (TBS), we found that there were no significant LTP differences between genotypes (Figure5E). Thus, these results demonstrate that loss of p35 resulted in a reduction in the postsynaptic response and selectively affected NMDAR-mediated LTD.
Biochemical analysis of hippocampal tissue from CreER-p35 cKO mice
When CaMKII is activated, CaMKII autophosphorylates at T286. We found that the phosphorylation level of pCaMKII (T286) was significantly elevated in CreER-p35 cKO mice when compared with control mice (Figure6C). We also analyzed phosphorylation level of CaMKII at T305, because previous study reported that activated CaMKII can promote either LTP or LTD depending on T305/T306 phosphorylation . pCaMKII (T305) was reduced in CreER-p35 cKO mice, although the difference was not statistically significant (p =0.338).
CREB is one of the transcriptional factors implicated in memory formation that is controlled by cAMP signaling. We found no difference in the phosphorylation level of pCREB (S133) between CreER-p35 cKO and control mice (Figure6D). These results suggest that the impaired spatial learning and memory and defective NMDAR-dependent LTD induction observed in CreER-p35 cKO mice are unrelated to cAMP signaling and the phosphorylation of CREB.
Our findings implicate Cdk5/p35 in spatial learning and memory, anxiety-like behavior, LTD induction, and the maintenance of spine density on hippocampal CA1 pyramidal neurons. These phenotypes of CreER-p35 cKO mice are similar to those of p35 KO mice  and CaMKIIcre-Cdk5 cKO mice , while they contradict findings from inducible Cdk5 cKO mice . In inducible Cdk5 cKO mice, increased NR2B in the postsynaptic membrane may lead to unexpected phenotypes that include improved learning and memory . Thus, the phenotype of inducible Cdk5 cKO mice did not represent a loss of Cdk5 kinase function . CaMKIIcre-Cdk5 cKO mice exhibited impaired learning and memory with impaired cAMP signaling . Since rolipram, an inhibitor of PDE4 and activator of cAMP signaling, rescued impaired learning and memory and hippocampal LTP, this phenotype is explained by impaired cAMP signaling . In p35 KO mice, histological abnormalities make it uncertain that the observed phenotypes, including impaired spatial learning and memory, are caused by Cdk5/p35 loss-of-function of . Our present study clearly supports the idea that Cdk5/p35 is required for spatial learning and memory .
Interestingly, defective LTD, but normal LTP in CA1, and the impairment of spatial learning and memory were also observed in p35 KO  and p35 cKO mice (Figure5). In mice lacking GluN2B, also known as NR2B, pyramidal neurons in the cortex and hippocampal CA1 had defective NMDA-dependent LTD and impaired spatial learning and memory . However, we found comparative protein levels of NR2B in the hippocampi of CreER-p35 cKO mice (Figure6A). There are several explanations for impaired induction of LTD with the loss of Cdk5/p35. Cdk5 and calcineurin are implicated in the interaction of phosphatidylinositol 4-phosphate 5-kinase γ661 (PIP5Kγ661) and the clathrin adaptor protein complex AP-2, resulting in the internalization of AMPA receptors during LTD in the CA1 ,. When the phosphorylation/dephosphorylation balance of PIP5Kγ661 is impaired, internalization of AMPA receptors in LTD will be compromised in the hippocampal CA1 of p35 cKO mice. The dephosphorylation of cofilin is required for NMDA receptor-dependent LTD in the CA1 . Furthermore, the phosphorylation of cofilin is upregulated by the treatment of a Cdk5 inhibitor, suggesting that Cdk5 regulates NMDA receptor-dependent LTD in the hippocampal CA1 through cofilin . In addition, Cdk5/p35 phosphorylates a number of postsynaptic proteins, including PSD-95 , Polo-like kinase 2 , NMDA receptors , and calcium channels. Reduced phosphorylation of these proteins may affect LTD induction. These possibilities should be tested in future experiments.
Cdk5 is involved in dendritic spine formation through the phosphorylation of ephexin1, WAVE1, and TrkB ,,. EphA4, which is activated by the phosphorylation of ephexin1 by Cdk5, is also necessary for synaptic plasticity in the amygdala . Another study suggests that the phosphorylation of TrkB by Cdk5 is required for spatial memory and hippocampal LTP . These studies reveal that spine formation, memory formation, and synaptic plasticity are closely related to each other. Our analysis of p35 cKO mice also identified reduced dendritic spines in pyramidal neurons in the cerebral cortex and hippocampal CA1 region (Figure4). Therefore, defective synaptic plasticity, in addition to a reduction in spine density, is related to the behavioral changes that we observed in p35 cKO mice. It is also possible that the loss of dendritic spine densities in CA1 pyramidal neurons is one of the reasons why the input-output curve in CreER-p35 cKO mice is lower than that in control mice (Figure5), as fewer dendritic spines on CA1 pyramidal neurons leads to decreased postsynaptic responses . Reduction of dendritic spine densities of CA1 pyramidal neurons seems cell-autonomous because we observed similar reduction of spine density of these neurons in CA1-specific p35 cKO mice .
The GluR1 subunit is essential for LTP in the CA1 region of the adult hippocampus . The phosphorylations of GluR1 at two sites, S831 by CaMKII and PKC and S845 by PKA, have been demonstrated to play a role in synaptic AMPA receptor regulation and synaptic plasticity ,. Our biochemical analysis revealed elevated phosphorylation of GluR1 at S831, but not at S845, in hippocampal homogenates from CreER-p35cKO mice (Figure6). We also found elevated phosphorylation of CaMKIIα at T286 (Figure6), suggesting an activated state of CaMKIIα ,. Previous studies have demonstrated the interaction between p35 and CaMKIIα  and elevated phosphorylation of CaMKIIα at T286 with the Cdk5 inhibitor, roscovitine . Therefore, our results indicate that loss of p35 releases its inhibitory function on CaMKIIα and results in elevated phosphorylation of GluR1 at S831 (Figure6). These biochemical changes may explain the lower LTP induction threshold observed in p35 KO mice . Although the role of CaMKII activation in LTP have been extensively characterized, much less is known about its role in LTD. Pi et al. have reported that activated CaMKII can promote either LTP or LTD depending on T305/T306 phosphorylation . Interestingly, we found a reduction of T305 phosphorylation of CaMKIIα in hippocampal homogenates from CreER-p35cKO mice (Figure6). This phosphorylation site of CaMKIIα inhibits its kinase activity ,, suggesting an activated state of CaMKII. Phosphorylation of CaMKIIα at S567 has recently been implicated in LTD . Thus, the relation between CaMKII activation and LTD induction warrants further investigation.
p25 is formed by the truncation of the N-terminus of p35 by calpain, and it activates Cdk5 by complexing with it to form Cdk5/p25. In previous studies, both overexpression and loss of p25 in the forebrain led to neuronal loss and neuroinflammation ,. Thus, tight regulation of Cdk5 is necessary to further study higher brain function without neuronal loss and neuroinflammation. In order to exclude the possibility that neuronal loss and neuroinflammation are the causes of this phenotype, Cdk5 cKO mice that were generated previously should be re-evaluated from the viewpoint of neuronal loss and neuroinflammation. Importantly, in our study, loss of Cdk5/p35 results in a disturbance of synaptic plasticity without neuronal loss and neuroinflammation (Additional file 3: Figure S3).
In a recent study, the impairment of neurotransmitter release was observed in a forebrain-specific Cdk5 cKO, indicating defective presynaptic function with Cdk5 loss-of-function . Therefore, we need to dissect the separate pre- and postsynaptic functions of Cdk5. As for postsynaptic function, we recently generated L7cre-p35 cKO mice, in which p35 is dramatically reduced in Purkinje cells in the cerebellum, and LTD induction was severely impaired in these Purkinje cells . The investigation into the role of Cdk5/p35 in postsynaptic plasticity in the hippocampus by using CA1 specific cre mice will provide further insight into the role of Cdk5 on synaptic plasticity in vivo.
The phosphorylation of various substrates by Cdk5 crucially affects synaptic plasticity, spine morphology, and memory formation, ultimately influencing behavior. It remains to be elucidated how Cdk5 controls different forms of neural plasticity via its phosphorylation of diverse proteins. Our findings on the role of Cdk5/p35 in LTD in the hippocampus allow a better understanding of the molecular mechanisms underlying synaptic plasticity and memory formation.
To investigate the role of Cdk5/p35 in higher brain function without histological abnormalities, we generated CreER p35 cKO mice. CreER-p35 cKO mice exhibited defective spatial learning and memory. Our analyses also revealed reduced spine density of pyramidal neurons, reduced sensitivity to synaptic input, and impaired LTD induction in hippocampal CA1. These results indicate that the kinase function of Cdk5/p35 is essential for normal synaptic function, and spatial learning and memory.
Tamoxifen (Sigma, MO) was dissolved in 99.9% methanol in 100mg ± ml−1, where DMSO was added (99.9% methanol: DMSO =5:2). 10mg ± ml−1 solution was made in corn oil (Sigma, MO).
Generation of tamoxifen-induced p35 conditional KO mice
All experimental protocols were approved by Institutional Animal Care and Use Committees of Waseda University and RIKEN. Throughout the experimental procedures, all efforts were made to minimize the number of animals used and their suffering. Mice were fed ad libitum with standard laboratory chow and water in standard animal cages under a 12h light/dark cycle.
p35-flox mice were generated as described on a C57BL/6 background . CAGGCre-ER (CreER) mice  were obtained from Jackson laboratory (stock number 004682). By crossing p35flox/+ and CreER mice, p35-flox/flox; CreER mice were obtained. Cre activity was induced by oral administration of tamoxifen (3mg ± 40g−1 body weight in corn oil) daily for three days. The resultant inducible p35 conditional KO mice were used as CreER-p35 cKO mice along with littermate controls that were given same tamoxifen treatment.
Hippocampi of the mice were collected from p35 cKO mice (n =4) and their p35-flox littermates (n =4) as controls at 6months old. Western blotting analysis was conducted as previously described . Primary antibodies used in present study are as follows; polyclonal antibody against p35 (C-19, 1:1000, Santa Cruz), anti-NR2B (1:1000, Cell signaling technology), anti-CREB (1:1000, Cell signaling technology), anti-pCREB (S133, 1:1000, Cell signaling technology), anti-GluR1 (1:1000, Cell signaling technology), anti-pGluR1 (S831/S845, 1:1000, Upstate), anti-CaMKII (1:1000, Chemicon), anti-pCaMKII (T286, 1:1000, Cell signaling technology), anti-pCaMKII (T305, 1:1000, Upstate) and anti-actin (1:1000, Sigma). Statistical analysis was conducted using the Students t test and mean ± standard error of the mean (S.E.M.) are shown on the graph. p<0.05 was considered to be statistically significant.
Spine density analysis
For modified GolgiCox staining, an FD Rapid Golgi Stain kit was used according to manufacturers instructions (FD NeuroTechnologies, MD). Stained slices were sectioned at a thickness of 150μm. Pyramidal neurons of hippocampal CA1 and layer V in cerebral cortex from each mouse were selected and the number of spines in apical dendrites of the neurons in hippocampal CA1 and in basal dendrites of the neurons in layer V in the cerebral cortex were counted using a BX50 microscope (Olympus, Japan) with UPlanSApo 40 (NA =0.95) objective. In a typical experiment, over 2000 spines were counted on more than 50 dendritic segments in 25 neurons for each sample. Statistical analysis was conducted by the Students t test, and the mean ± S.E.M. are shown on the graph. p<0.05 was considered to be statistically significant.
Electrophysiological experiments were conducted with 22.5month-old male mice 25 weeks after oral administration of tamoxifen. Mice were deeply anesthetized with halothane (2-Bromo-2-chloro-1, 1, 1-trifluoroethane) and killed by decapitation. The brains were immediately removed and placed in an ice-cold cutting solution [containing (in mM) sucrose 200, KCl 3, NaH2PO4 1, MgSO4 10, CaCl2 0.2, NaHCO3 26, and d-glucose 10, saturated with 95% O2 and 5% CO2]. Transverse hippocampal slices (300μm thick) were prepared from both hemispheres. The slices were incubated in the recording solution [containing (in mM) NaCl 120, KCl 3, NaH2PO4 1, MgSO4 1.25, CaCl2 2.5, NaHCO3 26, and d-glucose 10, saturated with 95% O2 and 5% CO2] at room temperature (25C) for at least 1h before recording.
Field potential responses were recorded from the stratum radiatum area in the CA1, using an array of 64 planar microelectrodes (MED-P515A) arranged in an 8 ± 8 pattern with an interelectrode spacing of 150μm (Alpha Med Scientific Inc.). Schaffer collaterals were stimulated at 0.05Hz by delivering biphasic current pulses (519–A, 0.2ms). Input-output relationships were measured as previously described . For paired-pulse facilitation (PPF) and long-term potentiation (LTP), the stimulation intensities were chosen to produce an excitatory postsynaptic potential (fEPSP) with 30% amplitude of the maximal response. The PPF was induced by paired stimuli with increasing intervals from 25400ms. The facilitation ratio was calculated as described . Long-term potentiation (LTP) was induced with 3 theta burst stimulations at 0.05Hz after 20min of stable baseline recording. Each theta burst consisted of 4 bursts (5Hz), each of which consisted of 4 pulses (100Hz). LTP was recorded for 60min after induction, and the potentiation was evaluated with the average slope of the last 5min recording (5660min). For long-term depression (LTD), the stimulation intensities were chosen to produce a fEPSP with 50% amplitude of the maximal response. LTD was induced by low frequency stimulation (1Hz, 1800s) in the presence of glutamate transporter inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid (tPDC, 300μM) . LTD was recorded for 60min after induction, and the depression was evaluated with the average slope of the last 5min recording (5660min). In a separate experiment examining if the LTD was NMDA receptor (NMDAR)-dependent, the NMDAR antagonist D-AP5 (50μM) was co-applied with tPDC. Evoked field responses were, through a 0.110kHz bandpass filter, recorded at a 20kHz sampling rate and stored for off-line analysis. All data were acquired and analyzed with a MED64 Mobius (Alpha Med Scientific Inc.). All experiments were performed by an investigator blind to the mouse genotype. Students t test was used for statistical analysis.
All experiments were performed by an investigator blind to the mouse genotype; 3mg ± 40g−1 body weight tamoxifen was given orally for three days to p35-flox and p35-flox; CreER male mice. After two weeks, 55.5month old male mice were subjected to behavioral analysis as described below (p35-flox: n = 6, CreER-p35 cKO: n = 7). Students t-test and one-way/two-way ANOVAs were used for statistical analysis.
The locomotor activity of each mouse was assessed with an open field (60 ± 60cm) at 55lx for 30min. The mice were placed in the center of the area, and their horizontal movements were registered with a set of cameras and analyzed with TimeOFCR4 software .
Elevated plus maze test
The elevated plus maze apparatus was set at a height of 50cm above the floor with 4 gray plexiglass arms, which were 2 opposite open arms (25cm ± 5cm) and 2 opposite closed arms (25cm ± 5cm ± 15cm). The apparatus was brightly illuminated (250lx) at the surface of each arm. Every mouse was placed in the center of the apparatus; their movement was measured for 10min, and analyzed with TimeEP1 software .
Morris water maze test
The Morris water maze test was performed as previously described with some modifications . In this study, we used a pool with diameter of 150cm. A circular platform (10cm in diameter) submerged ~0.7cm below the water surface was placed 37.5cm from the center of the pool to either north or south quadrants for counterbalancing samples. Mice were given 4 trials per day for 7 consecutive days in the hidden platform task under brightly illuminated conditions (250lx at the surface of maze). A randomly selected starting point along the rim of the maze was used for each of the four trials. A probe test was performed on day 8 after the acquisition session. In the probe test, the platform was removed from the tank and each mouse was allowed to swim for 60s. On day 10, mice were tested in a visible platform task for 3 consecutive days. In the visible platform task, the platform was made visible by attaching a black cubic landmark to the platform. Mouse movement in the water maze was recorded by a video camera and analyzed using NIH image WM software (OHara & Co.).
The data are presented as mean ± S.E.M., unless otherwise noted. The statistical analyses were performed using the Students t test, one-way ANOVA, or two-way repeated measures ANOVA as described in the Results or in the Figure legends. p<0.05 was considered statistically significant.
TM and XH established mutant mouse line. TM, NM and KS carried out the behavioral analysis. MT carried out electrophysiological studies. SI and TO participated in the design of the study. TM and SI performed the statistic analysis. TM and TO wrote he paper. All authors read and approved the final manuscript.
XH is now post-doctoral researcher at School of Life Sciences in Peking University.
TMs present address is Development Division, Novartis Pharma K. K.
Cyclin-dependent kinase 5
Excitatory postsynaptic potential
We thank N Kogo for technical assistance. This work was supported, in part by a Grant-in-Aid Fund of the Ministry of Education, Science, Technology, Sports and Culture of Japan and by a Waseda University Grant for Special Research Projects (2013A-051).
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