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J Neurosci. Author manuscript; available in PMC 2009 May 11.
Published in final edited form as:
PMCID: PMC2680063
EMSID: UKMS4661

Experience-dependent increase in CA1 place cell spatial information, but not spatial reproducibility, is dependent on the autophosphorylation of alphaCaMKII

Abstract

Place cells in hippocampal area CA1 are essential for spatial learning and memory. Here we examine whether daily exposure to a previously unexplored environment can alter place cell properties. We demonstrate two previously unreported slowly developing plasticities in mouse place fields: both the spatial tuning and the trial-to-trial reproducibility of CA1 place fields improve over days. We asked whether these two components of improved spatial coding rely on alphaCaMKII autophosphorylation, an effector mechanism of NMDA receptor-dependent long-term potentiation and an essential molecular process for spatial memory formation. We show that, in mice with deficient autophosphorylation of alphaCaMKII, the spatial tuning of place fields is initially similar to that of wild-type mice, but completely fails to show the experience-dependent increase over days. In contrast, place field reproducibility in the mutants, although impaired, does show the experience-dependent increase over days. Consequently, the progressive improvement in spatial coding in new hippocampal place cell maps depends on the existence of two molecularly-dissociable, experience-dependent processes.

Keywords: hippocampus, place cell, alphaCaMKII, plasticity

Introduction

Place cells are hippocampal pyramidal neurons that fire selectively when the animal is in a particular location within a particular environment (O’Keefe and Dostrovsky, 1971; O’Keefe and Nadel, 1978). Previous research in the rat has shown that, while some place field activity is present immediately in a novel environment, place field activity also undergoes significant development over the first few minutes of environmental experience (Hill, 1978; Frank et al., 2004; Wilson and McNaughton, 1993). The present study demonstrates two previously unreported slowly developing plasticities in place fields of the mouse, spatial tuning and spatial reproducibility, both of which improve over several days. We further show that they are differentially dependent on intracellular molecular mechanisms, spatial tuning being dependent on the switching properties of the alpha-isoform of the calcium/calmodulin-dependent protein kinase II (alphaCaMKII) and spatial reproducibility being independent of this property.

AlphaCaMKII plays a prominent role in plasticity at hippocampal glutamatergic synapses and in spatial memory formation (Elgersma et al, 2004). Crucially, alphaCaMKII can undergo autophosphorylation at threonine 286, allowing its kinase activity to switch from Ca2+-dependence to Ca2+-independence (Miller and Kennedy 1986). This molecular switch has been proposed to subserve synaptic information storage (Lisman et al., 2002) or memory formation (Irvine et al., 2006). Knock-in alphaCaMKIIT286A mutant mice, which have a targeted point mutation that inactivates the alphaCaMKII autophosphorylation, do not show NMDA receptor-dependent long-term potentiation (LTP) in hippocampal area CA1 (Giese et al., 1998; Yasuda et al., 2003; Lengyel et al. 2004; Cooke et al., 2006) and show profound behavioural deficits in the hippocampus-dependent, hidden-platform version of the Morris water maze task (Giese et al. 1998; Need and Giese, 2003; Morris et al. 1982).

Previous unit-recording studies have indicated the importance of alphaCaMKII functionality for the spatial properties of hippocampal place cells (Cho et al, 1998; Rotenberg et al, 1996). Neither study, however, addressed the temporal development of spatial firing. For instance, Cho et al (1998) reported that alphaCaMKIIT286A mutant place cells showed decreased spatial selectivity and stability, in an already-familiar radial arm maze, using a recording period of 30 minutes. This methodology could not distinguish between baseline deficits in spatial selectivity and reproducibility, and changes in these measures as a function of plasticity-dependent mechanisms. To address this question, we tracked place cell activity during the initial exposure to the recording enclosure and during the subsequent three days experience.

The present results show that, in wt mice, both the spatial tuning and reproducibility of CA1 place cells improve with experience over this four-day period. In contrast, in the alphaCaMKIIT286A mutants, only the reproducibility of CA1 place fields improves but not their spatial tuning.

Materials and Methods

Animals

Subjects were maintained on a 12 hr light/dark schedule (lights off at 3:00 P.M.). Animals weighed 25-35 g at surgery. After surgery, they were maintained at 90% of free feeding weight. Male homozygous alphaCaMKIIT286A (n = 7) mutants and control male wild-type (n = 4) littermates were obtained in the 129B6F2,3 background by intercrosses of heterozygous mutants. PCR genotyping was performed as previously described (Giese et al., 1998). All experiments were carried out blind to genotype and in accordance with the UK Animals (Scientific Procedures) Act 1986.

Surgery and electrodes

Mice under deep anaesthesia were chronically implanted with microdrives loaded with 4 tetrodes. Details of surgical procedure were similar to Cacucci et al. (2004), adapted for mice. Mice were allowed a 1-week postoperative recovery, after which microelectrodes were advanced ventrally by 30 μm/day. When hippocampal pyramidal cells were found, recording sessions began. After the experiments, the mice were perfused with 4% paraformaldehyde, the brain was sliced coronally into 40-μm sections and was stained with cresyl violet, for electrode localisation.

Behavioral testing

Experiments were conducted in a black-curtained, circular testing arena 1.7 m in diameter. Animals were given 5 recording trials per day for 4 days. All trials were 20 min duration with an inter-trial interval of 20 min. At all other times, mice were kept on a holding platform outside the arena. Recording environments were two identical circular-walled, light-gray wooden boxes (diameter 48 cm, height 36 cm), placed on a black platform that was washed between every trial. An external cue card (100 cm high; 80 cm wide) suspended inside the curtains provided directional constancy. During trials, the mouse searched for chocolate flakes randomly thrown into the environment. During cue rotation trials (4th trial of days 2 and 4) the cue card was rotated by 180° relative to the testing arena. All other cues remained constant.

Spike sorting

Isolation of single units from multi-unit data was performed manually, blind to genotype, on the basis of peak-to-trough amplitude, using custom software (TINT, Neil Burgess). Analysis of cluster quality, following Schmitzer-Torbert et al. (2005), ruled out unit isolation as a source of difference between the groups (see Supplementary Figure 1).

Quantitative analysis of place fields

Position data was sorted into 1.5 × 1.5 cm bins. Firing rate maps were constructed as described in Cacucci et al. (2004). On each trial, cells were included in the analysis if they had: a) spike width (time between peak and trough) > 300 μs and b) peak firing rate > 1 Hz. In general, different cells were recorded on each day. Occasionally, cells recorded on different days were judged to be the same, on the basis of stable spike clusters. In this case, only data from the first day’s recording were used.

Spatial information is a measure of the extent to which a cell’s firing can be used to predict the position of the animal. The estimate of the rate of information I(R|X) between firing rate R and location X proposed by Skaggs et al (1993) is:

I(RX)ip(xi)f(xi)log2(f(xi)F)
(1)

where p(xi) is the probability for the animal being at location xi, f(xi) is the firing rate observed at xi, and F is the overall firing rate of the cell. To obtain a measure of spatial information expressed in bits/spike we divided the value obtained from formula (1) by the overall mean firing rate F. The spatial information for each cell was the mean value for the first three trials of the day. Place field reproducibility was measured by correlating rate values of spatially corresponding bins from two consecutive trials, using only those bins in which firing rate > 0Hz in at least one trial. The reproducibility score for each cell was the mean r-value from the correlation of the 1st vs the 2nd trial, and the 2nd vs the 3rd trial, of the day. The spatial coherence for each firing rate map was computed as the mean correlation between the firing rate of each bin with the aggregate rate of the 24 nearest bins.

Results

Changes in place cell firing with repeated exposure to an environment

With repeated exposures to a cylindrical environment, place cells in wild-type mice increase their spatial tuning and reproducibility. Figure 1A shows the firing of three cells recorded over four consecutive days. On the first day each cell has a hotspot of elevated firing but there is a tendency for diffuse firing to occur over large parts of the environment. Over days, the area of the field tends to decrease and for some cells (eg cell 3) there is a marked increase in firing in the field. A measure which takes both these variables into account is the Skaggs information measure (Skaggs et al., 1993) which is shown beneath each firing rate map in Fig. 1A and plotted in Fig. 1B. At the same time, the reproducibility of the field location also increases (Fig. 1C). Although both measures are increasing over time and are correlated (r = 0.372, p < 0.001 for the whole cell population), it is clear that large increases in spatial information are compatible with small increases in reproducibility (eg cell 1 Day 1-2) and vice versa (eg cell 1 Day 2-3). This raises the question as to whether both types of plasticity are due to the same underlying mechanisms. We asked whether one or both types of plasticity rely on the autophosphorylation switch of alphaCaMKII by comparing the development of place fields in the alphaCaMKIIT286A mouse with those of wt mice.

The effects of experience on two spatial measures (spatial information, and spatial reproducibility) were examined during repeated exposures to the same cylindrical enclosure for 4 consecutive days. The total dataset consists of 226 mutant and 98 wt cells recorded from 7 mutant and 4 wt mice (littermate controls).

Hippocampal place cell spatial information in alphaCaMKIIT286A mice fails to improve with experience

As shown in Fig. 2A, place cell spatial information increased across days in wt mice confirming at the population level what we had seen for the individual cells shown in Figure 1. In contrast, spatial information did not change in the mutant mice during the same experience (two-way ANOVA: main effect of genotype, F1,314 = 29.69, p < 0.001; genotype-by-day interaction, F3,314 = 3.17, p = 0.025). The increase in spatial information over time in the wt mice is not likely to be due to non-spatial contributions to this measure. An analysis of variance on the mean running speeds revealed no difference in genotype (F1,36 = 2.14, p > 0.15) or genotype-by-day interactions (F3,36 = 0.3, p > 0.83), ruling out differences in running speed between the groups. We performed a similar analysis on total path length and find wt mice did not change the amount they sampled the environment across days (total path length, F3,13 = 0.16, p > 0.92), no difference between genotypes (F1,36 = 2.22, p > 0.15) and no genotype-by-day interaction (F3,36 = 0.35, p > 0.79). Moreover, no differences were observed across genotype or training day, in running speed variance (genotype, F1,36 = 2.0, p = 0.17; day, F3,36 = 0.01, p = 0.99) or angular head velocity (genotype, F1,36 = 2.09, p = 0.16; day, F3,36 = 0.85, p = 0.48).

On the other hand, we did find a significant overall difference in firing rate between genotypes (F1,314 = 3.71, p= 0.05) but no interaction between genotype and days (F3,314 = 0.13, p > 0.94) ruling out any systematic differential changes in firing rates as a causal explanation for our findings. Indeed, recalculating spatial information after deleting random spikes, in order to match mean firing rate across genotypes, does not alter the results (Supplementary Figure 2).

The experience-dependent effect on spatial information emerged by the second day. That is, while there was no difference in place cell spatial information in wt and mutants on day 1 (wt: 0.44 ±0.04 bits/spike, mut: 0.41 ±0.04 bits/spike, one-tailed t-test: t = 0.43, p = 0.33), there was a difference on day 2 (wt: 0.59 ±0.06 bits/spike, mut: 0.32 ±0.04 bits/spike, t = 3.58, p < 0.001).

As the effects described relate to differences across groups of animals, an alternative statistical approach is to analyse the data on a by-animal basis. Using this approach, the trends described above are still apparent (see Supplementary Figure 3A). There is a main effect of genotype (F1,36 = 20.74, p < 0.001) and an effect of day on the wild-type spatial information (F1,13 = 4.56, p < 0.029). However, there is no longer a significant genotype-by-day interaction (F1,36 = 1.87, p = 0.15).

Place field reproducibility is impaired in alphaCaMKIIT286A mice but improves with experience

Both wt and mutant place cells were tested for reproducibility of their firing patterns (Fig. 2B). Overall, mutant place fields show significantly lower trial-to-trial reproducibility scores than wild-type place fields when firing patterns recorded from temporally adjacent trials are compared (wt: 0.62±0.02, alphaCaMKIIT286A: 0.27±0.02, main effect of genotype: F1,224 = 98.87, p < 0.001). This indicates that place field reproducibility is compromised in the alphaCaMKIIT286A mice. In addition, however, there was also a significant effect of day on place field trial-to-trial reproducibility (main effect of day: F3,224 = 7.62, p < 0.001) and no interaction between genotype and days (F3,224 = 0.50, p > 0.68). This latter indicates that the reproducibility of both wt and mutant place fields increased in parallel over exposure days (wt: F3,76 = 4.33, p = 0.007; mutant: F3,148 = 6.05, p = 0.001), indicating that one form of plasticity is being spared in the alphaCaMKIIT286A mice (Fig. 2B and 2D). When spatial reproducibility is analysed by animal, the trends described above are still apparent (see Supplementary Figure 3B). There is still a main effect of genotype (F1,36 = 45.21, p < 0.001), however, there is no longer a significant effect of day (F1,36 = 1.81, p = 0.16).

Interestingly, spatial coherence, which is a measure of the local smoothness of place fields, although significantly impaired in alphaCaMKIIT286A place cells, improves over training, in a very similar manner to that observed for inter-trial spatial reproducibility (see Supplementary Figure 4).

alphaCaMKIIT286A place field impairments are not due to deficits in the head direction system

In order to test whether the spatial impairments observed in mutant place cells are caused by deficits of the head direction system or the anchoring of the place cells to the head direction system, cells were recorded while the cue card was rotated by 180° (see Methods). As shown in Figure 3, although place fields recorded from the alphaCaMKIIT286A mice appear less organised, they still follow the cue card rotation, like those recorded from the wt mice. This indicates that the mutant head direction system is still capable of correctly processing visual information and of using it as an orientation landmark.

The degree to which place cells were under the control of the cue card was assessed by comparing the angular displacement between sessions in 21 wild-type cells and 53 αCaMKIIT286A mutant cells. Cue-rotation firing rate maps were rotated in 6° steps, and correlated against baseline rate maps: the angular displacement was the rotation of maximum correlation. Place field angular displacement did not differ across genotype (wt mean vector ± circular sd 179.6° ±16.3°, αCaMKIIT286A 167.9° ±59.2°; Watson-Williams F-test, F1,73 = 1.01 p = 0.32).

An additional indication that the impaired reproducibility of αCaMKIIT286A place cells cannot be attributed to deficits in the head direction system was that, when rate maps from baseline trials were rotated as an ensemble, in order to maximise reproducibility, the reproducibility deficit observed in αCaMKIIT286A mice was not rescued (main effect of rotation in the αCaMKIIT286A mice, F1,296 = 2.21, p = 0.14; see Supplementary Figure 5).

Discussion

The present study shows that, upon exposure to a previously unexplored environment, both spatial information and spatial reproducibility of CA1 place cells increase over days in wild-type mice. We have also observed this progressive increase in both spatial measures in place cells in a different mouse strain to that used in the present study (C57BL/6 - Cacucci F, unpublished observations). A further novel finding is that these two plasticities are dissociable. In the absence of alphaCaMKII autophosphorylation at threonine 286, despite many repeated exposures to the same environment, hippocampal CA1 place fields do not show any increase in spatial information, but do show an increase in the place field reproducibility and spatial coherence.

The data were examined using either cells or animals as the experimental unit, the former assessing the effects of training and genotype on place cells as a population, the latter, their effects on the two groups of animals. The by-animal results are similar to the by-cell results (see Figure 2 and Supplementary Figure 3), although some effects do not reach statistical significance, possibly due to low statistical power. Unfortunately, the practical constraints of in vivo physiological recordings in mutant mice militate against the collection of datasets sufficiently large for satisfactory by-animal analysis (for further discussion of the choice of experimental unit see Leger and Didrichsons, 1994).

Few studies have addressed the temporal development of hippocampal place cell firing upon repeated exposures to the same environment over days. Hill (1978) reported that most place fields emerged immediately. Wilson and McNaughton (1993) found that the reconstruction of the rat’s position in a novel portion of an open field environment from CA1 place cell firing was more accurate during the second 10 minutes compared with the first 10 minutes of exposure. Kentros et al. (1998) showed that NMDA-R dependent mechanisms were required for CA1 spatial maps formed in a novel environment to be stable on the second day in that environment. Lee et al. (2004) suggested that CA1 might be less plastic than CA3 on the basis of their finding that the centre of mass of CA3 place fields shifts rapidly within the first day of exposure to a novel environment, while in CA1 the centre-of-mass shift only occurs on the second day of exposure. One study closely comparable to the present one is Frank et al. (2004), in which rats were exposed to the same novel environment for three days. The greatest changes to place fields were on day 1, but changes also occurred on day 2 if the rat was in the novel environment for <4 minutes on day 1. If day 1 exposure was >5 minutes, place fields were stable on day 2. In the present study, by contrast, place fields changed over four days, despite 100 minutes of training each day. While these few studies in different recording paradigms do not permit firm conclusions, they broadly indicate the importance of within-day plasticities in normal rat place cell function. The current study indicates that, in the mouse, CA1 place cell properties change over days. However, in the absence of a directly comparable study in the rat, it is not possible to conclude whether there is a species difference in the timescale of place field development. It would be interesting to test whether in the mouse this process might be modulated by the behavioural demands of the spatial task the animals are engaged in (Kentros et al., 2004).

In an important comparable exposure-to-novelty mouse study, Nakazawa et al. (2003), did not observe any progressive increase in CA1 place cell tuning in wild-type mice. The discrepancy could be due to the fact that their novel and familiar linear track environments shared extra-maze cues, whereas in the present study, the curtained recording arena provided a complete set of novel cues.

The present study is broadly consistent with previous mouse studies indicating the importance of alphaCaMKII functionality in spatial tuning and reproducibility of hippocampal place cells (Cho et al., 1998; Rotenberg et al., 1996). Place cells in mice expressing a constitutively active version of alphaCaMKII (alphaCaMKII-Asp286) showed reduced spatial coherence and impaired stability (Rotenberg et al., 1996) similarly to this study (see Figure 2 and Supplementary Figure 4). Cho et al. (1998) showed impaired spatial selectivity in alphaCaMKIIT286A mice during exposures to a familiar radial maze. An interesting aspect of the present results is that spatial coherence and across-trial reproducibility follow very similar trends, which may indicate that both measures are assessing the spatial reliability of firing, either across trial (spatial reproducibility) or within trial (spatial coherence). Perhaps both reflect a common neural mechanism.

Failure of spatial information to increase over a 4-day period in the mutant animals could be interpreted in terms of a deficit in NMDA-mediated plasticity. Conversely, the preserved increase in reproducibility and coherence suggests that some plasticity might be taking place at the level of CA1 place cells in the alphaCaMKIIT286A mice. One possibility is that these processes are supported at different synaptic loci within the hippocampus. For instance, NMDAR-dependent LTP at CA3-CA1 synapses is abolished in αCaMKIIT286A mice (Giese et al., 1998; Cooke et al., 2006) implying that any intra-hippocampal learning mechanisms reliant on NMDAR plasticity in CA3-CA1 circuits would be disrupted. However, medial entorhinal-dentate gyrus LTP is intact in αCaMKIIT286A mice (Cooke et al., 2006), allowing the reproducibility and coherence increases to be supported by plasticity at this synaptic site. Alternative possibilities are that the plasticities underlying spatial tuning and place field reproducibility/coherence take place at the same synaptic loci, but depend on different intracellular mechanisms, or that they might be supported by extra-hippocampal mechanisms perhaps in the medial entorhinal grid cell system (Fyhn et al., 2004).

The cue card rotation experiment supports the view that the deficits observed in αCaMKIIT286A place cells are not due to an impaired head direction system. Cue rotation is preserved in mutants, showing that the αCaMKIIT286A mouse head direction cells can use sensory stimuli as spatial landmarks, that the head-direction system can exert control over the place cells. It further suggests that there are no gross visual sensory impairments in the αCaMKIIT286A mouse.

In summary, this study demonstrates the existence of two slowly developing plasticities in mouse place fields, spatial tuning and spatial reproducibility, both of which improve over several days. Our findings indicate that deficient autophosphorylation of alphaCaMKII completely prevents the improvement in spatial tuning but, whilst impairing spatial reliability, does not prevent its experience-dependent improvement over days.

Supplementary Material

Supplementary Figures

Acknowledgements

This work was funded by a BBSRC project grants and by a Wellcome Trust program grant. We thank Stephen Burton and Jim Donnett for technical support and Neil Burgess and Ming Yi for helpful discussions. We thank Elaine E. Irvine for genotyping of the mice and Anna Need for providing them.

References

  • Cacucci F, Lever C, Wills TJ, Burgess N, O’Keefe J. Theta-modulated place-by-direction cells in the hippocampal formation in the rat. J. Neurosci. 2004;24:8265–8277. [PMC free article] [PubMed]
  • Cho YH, Giese KP, Tanila H, Silva AJ, Eichenbaum H. Abnormal hippocampal spatial representations in alphaCaMKIIT286A and CREBalphaDelta- mice. Science. 1998;279:867–869. [PubMed]
  • Cooke SF, Wu J, Plattner F, Errington M, Rowan M, Peters M, Hirano A, Bradshaw KD, Anwyl R, Bliss TV, Giese KP. Autophosphorylation of alphaCaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse. J. Physiol. 2006;574:805–818. [PubMed]
  • Elgersma Y, Sweatt JD, Giese KP. Mouse genetic approaches to investigating calcium/calmodulin-dependent protein kinase II function in plasticity and cognition. J. Neurosci. 2004;24:8410–8415. [PubMed]
  • Frank LM, Stanley GB, Brown EN. Hippocampal plasticity across multiple days of exposure to novel environments. J. Neurosci. 2004;24:7681–7689. [PubMed]
  • Fyhn M, Molden S, Witter MP, Moser EI, Moser MB. Spatial representation in the entorhinal cortex. Science. 2004;305:1258–1264. [PubMed]
  • Giese KP, Fedorov NB, Filipkowski RK, Silva AJ. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science. 1998;279:870–873. [PubMed]
  • Hill AJ. First occurrence of hippocampal spatial firing in a new environment. Exp Neurol. 1978;62:282–297. [PubMed]
  • Irvine EE, von Hertzen LS, Plattner F, Giese KP. alphaCaMKII autophosphorylation: a fast track to memory. Trends Neurosci. 2006;29:459–465. [PubMed]
  • Kentros C, Hargreaves E, Hawkins RD, Kandel ER, Shapiro M, Muller RV. Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science. 1998;280:2121–2126. [PubMed]
  • Kentros C, Agnihotri NT, Streater S, Hawkins RD, Kandel ER. Increased attention to spatial context increases both place field stability and spatial memory. Neuron. 2004;42:183–185. [PubMed]
  • Lee I, Rao G, Knierim JJ. A double dissociation between hippocampal subfields: differential time course of CA3 and CA1 place cells for processing changed environments. Neuron. 2004;42:803–15. [PubMed]
  • Leger DW, Didrichsons IA. An assessment of data pooling and some alternatives. Anim. Behav. 1994;48:823–832.
  • Lengyel I, Voss K, Cammarota M, Bradshaw K, Brent V, Murphy KP, Giese KP, Rostas JA, Bliss TV. Autonomous activity of CaMKII is only transiently increased following the induction of long-term potentiation in the rat hippocampus. Eur. J. Neurosci. 2004;20:3063–3072. [PubMed]
  • Lisman J, Schulman H, Cline H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat. Rev. Neurosci. 2002;3:175–190. [PubMed]
  • Miller SG, Kennedy MB. Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch. Cell. 1986;44:861–870. [PubMed]
  • Morris RG, Garrud P, Rawlins JN, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297:681–683. [PubMed]
  • Nakazawa K, Sun LD, Quirk MC, Rondi-Reig L, Wilson MA, Tonegawa S. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron. 2003;38:305–315. [PubMed]
  • Need AC, Giese KP. Handling and environmental enrichment do not rescue learning and memory impairments in alphaCamKII(T286A) mutant mice. Genes Brain Behav. 2003;2:132–139. [PubMed]
  • O’Keefe J, Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 1971;34:171–175. [PubMed]
  • O’Keefe, Nadel L. The Hippocampus as a Cognitive Map. Clarendon Press; Oxford: 1978.
  • Rotenberg A, Mayford M, Hawkins RD, Kandel ER, Muller RU. Mice expressing activated CaMKII lack low frequency LTP and do not form stable place cells in the CA1 region of the hippocampus. Cell. 1996;87:1351–1361. [PubMed]
  • Skaggs WE, McNaughton BL, Gothard KM, Markus EJ. An information-theoretic approach to deciphering the hippocampal code. Neural Information Processing Systems. 1993;5:1030–1037.
  • Shmitzer-Torbert N, Jackson J, Henze D, Harris K, Redish AD. Quantitative measures of cluster quality for use in extracellular recordings. Neuroscience. 2005;131:1–11. [PubMed]
  • Wilson MA, McNaughton BL. Dynamics of the hippocampal ensemble code for space. Science. 1993;261:1055–1058. [PubMed]
  • Yasuda H, Barth AL, Stellwagen D, Malenka RC. A developmental switch in the signaling cascades for LTP induction. Nat. Neurosci. 2003;6:15–16. [PubMed]