J Comp Physiol A (2014) 200:77–82 DOI 10.1007/s00359-013-0862-2

ORIGINAL PAPER

Both PKMf and KIBRA are closely related to reference memory but not working memory in a T-maze task in rats Dean-Chuan Wang • Pei-Chun Liu Hui-Shan Hung • Tsan-Ju Chen



Received: 22 August 2013 / Accepted: 9 October 2013 / Published online: 20 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013

Abstract Protein kinase M zeta (PKMf) and the kidney and brain protein (KIBRA) play important roles in various forms of memories. However, whether they are involved in performing the T-maze task is still unknown. In this study, the delayed nonmatch-to-sample (DNMS) task in a T-maze was given to rats. The percentage of correct choices denoting the performance accuracy was calculated and the protein levels of PKMf and KIBRA in rat’s prefrontal cortex were measured. The results showed significantly increased performance accuracy after the training phase, which was maintained on the next day in groups with a delay of 10 s but not 30 s, indicating that 30 s is too long for rats to maintain working memory. As for the expressions of PKMf and KIBRA, significant increases were observed 1 day after the training phase, indicating that the formation of reference memory accompanies an increase in PKMf and KIBRA. No significant difference was found among groups with various delay intervals, indicating that the expressions of PKMf and KIBRA exert no effects on the performance of working memory. These results provide the first evidence that KIBRA as well as PKMf is closely related to reference memory but not working memory in rats. Keywords T-maze  PKMf  KIBRA  Reference memory  Working memory D.-C. Wang Department of Sports Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan P.-C. Liu  H.-S. Hung  T.-J. Chen (&) Department of Physiology, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan e-mail: [email protected]

Introduction The molecular basis of learning and memory involves modification of synapse structure and strength in response to neuronal activity. Hippocampal long-term potentiation (LTP), an activity-dependent form of long-term synaptic enhancement, is the most commonly studied model of learning and memory. Although various kinds of molecules are important for the induction of LTP and the formation of long-term memory, inhibitors of these molecules usually did not disrupt the maintenance of LTP or the storage of long-term memory (Sanes and Lichtman 1999; Sacktor 2011). Recently, a candidate molecular mechanism for long-term memory storage has been identified as the persistent action of protein kinase M zeta (PKMf), a brainspecific protein kinase C (PKC) isoform (Pastalkova et al. 2006; Shema et al. 2007). The PKC family comprises conventional (a, bI, bII, c), novel (d, e, g, h) and atypical (f/k) PKCs. Most PKC isoforms consist of an N-terminal regulatory domain and a C-terminal catalytic domain (Nishizuka 1995). Under basal conditions, full-length PKC isoforms are inactive. Second messengers, such as diacylglycerol or Ca2?, bind to the regulatory domain leading to a conformational change that releases the autoinhibition and thus activate full-length PKCs. In contrast, PKMf is generated by new protein synthesis from PKMf mRNA that encodes only the f catalytic domain. As a result, PKMf is homolog to the catalytic domain of PKCf and thus constitutively and persistently active (Hernandez et al. 2003; Muslimov et al. 2004; Sacktor 2011). It has been demonstrated that the persistent activity of PKMf is both necessary and sufficient for the maintenance of LTP (Ling et al. 2002; Serrano et al. 2005) and long-term memories (Pastalkova et al. 2006;

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Serrano et al. 2008; Hardt et al. 2010; Migues et al. 2010; Li et al. 2011). In addition, the kidney and brain protein (KIBRA), predominantly expressed in the kidney and the memoryrelated brain regions (the hippocampus and the cortex) (Johannsen et al. 2008), has been reported to be a substrate of PKCf and PKMf (Bu¨ther et al. 2004; Yoshihama et al. 2012). KIBRA knockout mice have significant deficits in hippocampal LTP and have profound learning and memory defects, indicating that KIBRA is critical for synaptic plasticity and learning and memory (Makuch et al. 2011). These results provide a strong support for the finding of an association between KIBRA and the cognitive deficits observed in Alzheimer’s disease (Corneveaux et al. 2010; Schneider et al. 2010). Working memory refers to the temporary retention of information that was just experienced or just retrieved from long-term memory but no longer exists in the external environment (D’Esposito 2007; Touzani et al. 2007). The prefrontal cortex (PFC) has been found to be strongly implicated in working memory processes (Dalley et al. 2004). To evaluate PFC-mediated working memory, the delayed nonmatch-to-sample (DNMS) task has been confirmed sensitive to the impairment of working memory related to PFC damage in mammals (Markowitsch and Pritzel 1977). In rodents, working memory is usually tested by the DNMS task in a T-maze (Mizoguchi et al. 2000, 2004; Dalley et al. 2004), in which reference memory is also involved (Mizoguchi et al. 2004). Reference memory is a memory for the ‘rules’ of a given task, which is typically acquired with repeated training and would persist from days to months (Dudchenko 2004). Even though both PKMf and KIBRA play important roles in various forms of memories, whether they are involved in the performance of DNMS task in a T-maze is still unknown. The results of this study provide the first evidence that both PKMf and KIBRA are closely related to the reference memory but not the working memory when performing a DNMS task in a T-maze.

T-maze task

Materials and methods

Western blot analysis

Animals

One hour after the 4-d habituation phase or the last test run, rats were sacrificed with CO2 inhalation and their brains were quickly removed. Under dissection microscope, the frontal cortices containing medial PFC were isolated and homogenized in lysis buffer. Proteins were obtained by centrifugation at 19,500g for 20 min at 4 °C and separated

Male Sprague–Dawley rats were obtained from BioLasco Taiwan Co., Ltd. and housed in cages individually in a temperature- and humidity-controlled room with a 12-h light/dark cycle.

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A T-maze apparatus (stem arm, 30 (L) 9 12 (W) 9 15 (H) cm; two branch arms, 60 (L) 9 12 (W) 9 15 (H) cm each) equipped with three sliding doors was used (Fig. 1a). The stem arm was the place where the rat started free explorations or trials. To increase animals’ motivation for food, they were fed with a restricted amount of chow (*90 % of the normal intake) throughout the experiment (Mizoguchi et al. 2000). Water was always available in the home cage. After 7 days of initial handling (5 min/day), the rat aged 12 weeks was habituated to the T-maze apparatus for 4 days (five explorations/day) (Fig. 1b). During each 5-min exploration, the rat was allowed to explore freely in the T-maze with all sliding doors open and eat food pellets available at the end of both branch arms. After habituation, the rats were trained to perform the nonmatch-to-sample (NMS) task, in which a trial consisted of an ‘‘information run’’ and a ‘‘test run’’. In the information run (I), one branch arm was blocked forcing the animal into the open branch arm, whereupon the animal received one food pellet. After that, the test run (T) followed immediately, the block was removed and the rat was returned to the stem arm and given a free choice of either branch arm. Rats received one food pellet for choosing the previously unvisited arm (correct choice), whereas choosing the previously visited arm yielded no reward (Fig. 1b, c). Left/right allocations for the information and test runs were pseudo-randomized over ten trials per day, with no more than three consecutive information runs to the same side. The intertrial interval was 1 min. After 4 days of training, the percentage of correct choices C70 % for two consecutive days was required to reach criterion for the following evaluations. Animals that did not reach this criterion were discarded. On the next day (day 9), the DNMS task was performed to evaluate animal’s working memory. Rats were assigned randomly to one of three groups in which ten trials with a delay of zero (for comparison), 10 or 30 s (denoted as D0, D10 and D30, respectively) between the information run and the test run were given. The percentages of correct choices were calculated for comparison.

J Comp Physiol A (2014) 200:77–82 Fig. 1 The T-maze apparatus and the experimental schedule and procedure. a The T-maze apparatus is illustrated. b An experimental timeline shows the experimental design and schedule. H habituation, IT a trial consisting of an information run and a test run, D delay. Upward arrows indicate the time points for analyzing the behavioral performance of the T-maze task. c The experimental procedure for performing one trial of the DNMS task in a T-maze is illustrated

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by SDS-PAGE (NuPAGEÒ Novex 10 % Bis–Tris gel, Invitrogen) in MOPS SDS running buffer (NuPAGEÒ MOPS SDS Running Buffer, Invitrogen). Subsequently, proteins were transferred onto polyvinylidene difluoride (PVDF) membranes and probed with rabbit polyclonal antibodies that recognize the C-terminus of PKCf (1:1,000) (sc-216, Santa Cruz, Dallas, TX, USA), KIBRA (1:100) (sc-133373, Santa Cruz, Dallas, TX, USA) and GAPDH (1:5,000) (GTX100118, GeneTex, Irvine, CA, USA). After being incubated with the horseradish peroxidase-conjugated anti-rabbit IgG (1:4,000) (Chemicon, Temecula, CA, USA), blots were developed with enhanced chemiluminescence reagents (Perkin Elmer, Norwalk, CT, USA) and the results were recorded on X-ray film. Immunoreactivity was quantified using densitometric analysis. Statistical analysis Statistical comparisons were made using the one-way ANOVA and post hoc test (LSD test). All data are presented as mean ± SEM. In all cases, p \ 0.05 is considered statistically significant.

Results Working memory presented in the DNMS task with a delay of 10 s was lost when extending the delay interval to 30 s To evaluate the performance accuracy in the T-maze task, the percentage of correct choices was calculated. During the 4-d training phase, the rat was trained to perform the NMS task. The average percentage of correct choices was increased significantly from 64.17 ± 3.61 % on the first day (IT1) to 81.33 ± 2.73 % on the fourth day (IT4) (Fig. 2), indicating that the reference memory has been formed. On the next day, the DNMS task with no delay (for comparison) or a delay of 10 or 30 s was given to these trained rats. As shown in Fig. 2, when compared with the baseline level (IT1), the average percentages were maintained at a significantly increased level in groups with no delay (D0, 83.33 ± 3.33 %) or a delay of 10 s (D10, 82.00 ± 4.89 %), whereas no significant difference was found in the group with a delay of 30 s (D30, 60.00 ± 5.77 %), indicating that rat’s working memory

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Correct choices (%)

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Fig. 2 The performance accuracy of the T-maze task. After performing the T-maze task, the percentage of correct choices was calculated to evaluate the performance accuracy. All data are expressed as mean ± SEM. Group sizes: IT1 (N = 15), IT4 (N = 15), D0 (N = 4), D10 (N = 5), D30 (N = 6). **p \ 0.01, ***p \ 0.001 relative to IT1. ##p \ 0.01, ###p \ 0.001 relative to D30

PKM (% control)

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was intact when performing the DNMS task with a delay of 10 s but was lost when extending the delay interval to 30 s. Expressions of PKMf and KIBRA were enhanced 1 day after the 4-d training phase irrespective of the delay intervals for performing the DNMS task The expressions of PKMf and KIBRA in rat PFC were examined by Western blot analysis to evaluate the changes of these two proteins. Five groups were included for comparison. Age-matched naive control rats always stayed in their home cages. The second group consisted of rats that encountered 4-d habituation phase (H4). The rest three groups were given the T-maze task with no delay or a delay of 10 or 30 s 1 day after the 4-d training phase (D0, D10 and D30). As shown in Fig. 3, compared with the naive control group (normalized to 100 %), the expressions of PKMf in groups of D0, D10 and D30 were significantly increased (156.18 ± 9.93, 187.70 ± 21.51 and 170.70 ± 12.32 %, respectively). In addition, the levels of PKMf in groups of D10 and D30 were significantly higher than that of H4 group (130.54 ± 2.88 %). As for the expression of KIBRA, the levels in groups of D0, D10 and D30 were significantly increased (437.63 ± 67.15, 423.80 ± 51.59 and 379.94 ± 53.53 %, respectively) when compared with the naive control group (normalized to 100 %). In addition, the levels of KIBRA in groups of D0, D10 and D30 were significantly higher than that of H4 group (187.35 ± 42.17 %). Although there is a trend of increase in the levels of PKMf and KIBRA after the 4-d habituation phase (H4), no statistical significance was found. These results indicate

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Fig. 3 The changes in the protein levels of PKMf and KIBRA following the habituation and training phases. a Representative blots were shown. GAPDH was used as loading control. b, c Protein levels of PKMf and KIBRA in naive control rats were normalized to 100 %. All data are expressed as mean ± SEM. Group sizes: Naive control (N = 4), H4 (N = 4), D0 (N = 4), D10 (N = 4), D30 (N = 4). **p \ 0.01, *** p \ 0.001 relative to the naive control group. # p \ 0.05, ##p \ 0.01 relative to H4

that the training phase but not the habituation phase is required to enhance the protein levels of PKMf and KIBRA.

Discussion The DNMS task in a T-maze was given to rats to evaluate their working memory. Compared with the baseline level at

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the beginning of the training phase (IT1), the significantly increased performance accuracy of the trained rats (IT4) was maintained under a condition with a delay of 10 s (D10) but not 30 s (D30) (Fig. 2), indicating that a delay of 30 s is too long for rats to maintain their working memory. This finding is parallel to that shown in previous studies. Although, they did not indicate a significant difference in the performance accuracy within naive or sham-operated control group with several delay intervals (10, 30 and 60 s), the results shown in their figures revealed a marked reduction at a delay of 30 or 60 s (Fig. 1 in Mizoguchi et al. 2000; Fig. 2 in Mizoguchi et al. 2004; Fig. 1 in Mizoguchi et al. 2009). Based on the evidence that, during hippocampal LTP, tetanic stimulation induces de novo synthesis of PKMf within 1 h through increased translation of preexisting PKMf mRNA that has been transported to the dendrites of neurons after being generated (Hernandez et al. 2003; Muslimov et al. 2004), rats in the present study were sacrificed 1 h after the last test run in the T-maze to examine the protein expression. The protein levels of both PKMf and KIBRA in rat’s PFC were significantly increased under a condition with no delay 1 day after the 4-d training phase (D0), whereas no significant change was found following the 4-d habituation phase (H4) (Fig. 3). This finding indicates that the 4-d training phase but not the 4-d habituation phase is required for enhancing the expressions of PKMf and KIBRA. Most importantly, this enhancement was also observed in rats performing the DNMS task with a delay of 10 and 30 s (D10 and D30) and no significant difference was found among groups of D0, D10 and D30 (Fig. 3), indicating that the delay intervals are not related to the expressions of PKMf and KIBRA. Therefore, it is suggested that following the 4-d training phase, the reference memory was formed and simultaneously the expressions of PKMf and KIBRA were increased, which were still maintained on the next day. Furthermore, although, the working memory did not persist for 30 s in rats (Fig. 2), the expressions of PKMf and KIBRA were significantly increased at delay intervals of 0, 10 and 30 s (Fig. 3), suggesting that enhanced expressions of PKMf and KIBRA are not required for the performance of working memory. A similar finding has been reported that PKMf activity in the rat dorsal hippocampus was required for spatial reference memory but not spatial working memory in a radial arm maze (Serrano et al. 2008). The authors suggested that memories unaffected by PKMf inhibitor in the dorsal hippocampus may be stored elsewhere (Serrano et al. 2008). In fact, the hippocampus has been reported to work closely with the PFC in the formation of working memory (Becker and Morris 1999). However, the results here reveal that, although the expression of PKMf in rat’s PFC was significantly enhanced, working memory was lost following a

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delay of 30 s. As for the contribution of KIBRA, less direct evidence has been reported. In patients with Alzheimer’s disease, the expression of KIBRA is significantly altered in key brain regions (Corneveaux et al. 2010). A recent metaanalysis study suggested an association of KIBRA with working memory in humans (Milnik et al. 2012), however, no evidence has been shown in rodents. PKMf activity is required in a positive feedback loop to maintain increased amounts of PKMf (Sacktor 2010), therefore, inactivation of PKMf in the PFC may further clarify whether the performance accuracy of the T-maze task is increased through enhancing the expression of PKMf. A commonly used PKMf inhibitor is ZIP (zeta inhibitory peptide) (Sacktor 2011; Yao et al. 2013). However, the specificity of ZIP for inhibiting PKMf has been called in question (Lisman 2011; Wu-Zhang et al. 2012). In particular, two recent studies found that, in PKCf/PKMf knockout mice, ZIP still reversed LTP and inhibited memory in these knockout mice, indicating that the effects of ZIP occur through PKMf-independent mechanisms (Lee et al. 2013; Volk et al. 2013). In fact, these knockout mice have unimpaired learning and memory and normal synaptic transmission and LTP (Lee et al. 2013; Volk et al. 2013), indicating that unknown compensatory effects may exist. Therefore, the development of other reagents for inactivating PKMf will be helpful for studying the role of PKMf. In summary, the present study provides the first evidence that enhanced expressions of both PKMf and KIBRA in rat’s PFC are closely related to reference memory but not working memory in a T-maze task. Acknowledgments This work was supported by a grant from the Kaohsiung Medical University Research Foundation (KMUM110003), Taiwan. All experimental procedures have been reviewed and approved by the Animal Care and Use Committee of the Kaohsiung Medical University.

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Both PKMζ and KIBRA are closely related to reference memory but not working memory in a T-maze task in rats.

Protein kinase M zeta (PKMζ) and the kidney and brain protein (KIBRA) play important roles in various forms of memories. However, whether they are inv...
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