Impaired cerebellar Purkinje cell potentiation generates unstable spatial map orientation and inaccurate navigation - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 May 21;10(1):2251.
doi: 10.1038/s41467-019-09958-5.

Impaired cerebellar Purkinje cell potentiation generates unstable spatial map orientation and inaccurate navigation

Julie Marie Lefort  1 , Jean Vincent  1 , Lucille Tallot  1 , Frédéric Jarlier  1 , Chris Innocentius De Zeeuw  2   3 , Laure Rondi-Reig  4 , Christelle Rochefort  1
Affiliations

Impaired cerebellar Purkinje cell potentiation generates unstable spatial map orientation and inaccurate navigation

Julie Marie Lefort et al. Nat Commun. .

Abstract

Cerebellar activity supported by PKC-dependent long-term depression in Purkinje cells (PCs) is involved in the stabilization of self-motion based hippocampal representation, but the existence of cerebellar processes underlying integration of allocentric cues remains unclear. Using mutant-mice lacking PP2B in PCs (L7-PP2B mice) we here assess the role of PP2B-dependent PC potentiation in hippocampal representation and spatial navigation. L7-PP2B mice display higher susceptibility to spatial map instability relative to the allocentric cue and impaired allocentric as well as self-motion goal-directed navigation. These results indicate that PP2B-dependent potentiation in PCs contributes to maintain a stable hippocampal representation of a familiar environment in an allocentric reference frame as well as to support optimal trajectory toward a goal during navigation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The stability of spatial map orientation is altered in L7-PP2B mice. a Examples showing 3 place cells recorded during two consecutive identical sessions S1 and S2 in light conditions for control (top) and L7-PP2B mice (bottom). The place cell from the top right illustrates one of the rare examples of a control place cell that was unstable between S1 and S2 (5%) whereas two examples of L7-PP2B place cells displaying instability are shown below (25% of recordings). The animal’s path is shown in black and spike locations in red, with a color-coded map of the firing rate below (peak rate is indicated above the map). Cell identity is indicated between trajectories. S1–S2 similarity coefficients are indicated between rate maps. b, c Distribution of S1–S2 similarity coefficients in the whole population of place cells recorded in control (b) and L7-PP2B (c) mice. These distributions are significantly different between control and L7-PP2B mice, Kolmogorov–Smirnov, p < 0.001. d, e Classification of recorded cells into stable and unstable neurons with respect to the S1–S2 angle and S1–S2 similarity coefficient in both control (d) and mutant (e) mice. The classification has been achieved with a K-means algorithm using the two dimension vectors [S1–S2 angle; S1/S2 similarity coefficient] (see Methods). Each dot represents an isolated place cell. Unstable cells are color-coded with a common color for cells recorded in the same session (indicated on the right). f Pie-chart illustrating the proportion of unstable recordings for controls (left) and mutants (right) in orange. Unstable recordings occurred more frequently in mutant mice than in controls (18/73 versus 3/57, p = 0.003, χ2 test). A recording episode was classified as unstable if more than 50% of the recorded place cells were classified unstable (see Methods). In a majority of recordings (non-hatched areas) several cells were simultaneously recorded, which allowed subsequent analyses. g Polar histogram displaying the median rotation angle calculated for each unstable S1–S2 recording in control and L7-PP2B mice
Fig. 2
Fig. 2
Spatial map rotation is associated with increased cue exploration. a Examples of control and L7-PP2B mice running tracks during the first 2 min of exploration in consecutives stable sessions, or in sessions associated with spatial map rotation (SSMR). b–g Scatterplot showing the mean distance from the cue (b, c), the % of time in the cue zone (d, e) and the number of entries in the cue zone, normalized by the traveled distance (f, g) in stable sessions and in SSMR. Basal characterization of cue behavior during the 1st session of stable sessions showed a tendency in L7-PP2B mice to explore more the object than controls (mean distance from the cue, U = 1681, p = 0.011; % of time spent in the cue zone, U = 2080, p = 0.44; normalized number of entries in the cue zone, U = 1349, p < 0.001). An increase in cue behavior was observed in L7-PP2B mice, in S2 relative to S1 during SSMR, but not during stable sessions (mean distance from the cue: stable sessions Z = 0.82, p = 0.82; SSMR, Z = 3.24, p = 0.0024; % of time in the cue zone: stable sessions Z = 0.20, p = 0.17; SSMR, Z = 2.37, p = 0.0368; normalized number of entries in the cue zone: stable sessions Z = 0.017, p = 1; SSMR, Z = 2.77, p = 0.011, Wilcoxon Signed-Rank test). h–j S2/S1 ratio of the mean distance from the cue (h), the percentage of time in the cue zone (i), and the normalized number of entries in the cue zone (j) in controls and L7-PP2B mice. In L7-PP2B mice, all parameters were modified in SSMR compared to stable sessions (mean distance from the cue, U = 275, p = 0.010; % of time in the cue zone, U = 281, p = 0.012; normalized number of entries in the cue zone, U = 267, p = 0.0072, Mann–Whitney U test). In control mice, no statistical comparison was applied given the low sample size of unstable cells. p values were adjusted for multiple comparisons with a Bonferroni correction. N and n indicate mice and cell number, respectively. Error bars represent S.E.M.
Fig. 3
Fig. 3
Hippocampal place cell properties of L7-PP2B mice are preserved in the dark. a Schematic diagram of the protocol used to assess the effect of proximal cue removal on place cell properties. After two consecutive standard sessions (S1–S2), the cue was removed and light was turned off (S3–S4). The mouse was removed from the arena after S4, and S5 was run similarly to S1–S2. b Examples of color-coded rate maps showing firing activity of control and L7-PP2B single CA1 pyramidal cells over the five consecutive sessions. c–f Barplot showing place cell characteristics during familiar sessions (light, S1–S2) or during proximal cue suppression (dark, S3–S4) in control and L7-PP2B mice. Field size was higher in L7-PP2B compared to controls in both light and dark condition (c, genotype, F(1,110) = 16.5, p < 0.001; session, F(1,110) = 0.63, p = 0.43, session*interaction, F(1,110) = 3.70, p = 0.057, repeated measure ANOVA) but no difference between light and dark conditions was observed in L7-PP2B mice (p = 0.46, LSD post-hoc test). Spatial coherence (d, genotype F(1,110) = 0.44, p = 0.51, repeated measure ANOVA) spatial information content (e, genotype F(1,110) = 0.38, p = 0.54, repeated measure ANOVA), or intra-session stability (f, light: U = 1372, p = 0.55, dark: U = 1546, p = 1, Mann–Whitney U-test with p values adjusted for multiple comparisons) were all similar between control and mutant mice in both sensory conditions. Error bars represent S.E.M.
Fig. 4
Fig. 4
Instability occurs upon entry in a familiar environment. a Examples of color-coded firing maps of two simultaneously recorded L7-PP2B place cells over the five consecutive sessions, for which instability occurred both at S1–S2 and S4–S5 transitions. b Barplot showing inter-session similarity coefficient for control and L7-PP2B place cells at S1–S2 and S4–S5 transitions, i.e., at transitions corresponding to entries into the arena. Cells from stable recordings (white for controls, black for mutants) are separated from cells from unstable recordings identified at S1–S2 transition (orange for mutants). In this protocol, no recording showed S1–S2 instability in control mice. c Instabilities at S4–S5 transition occurred only in L7-PP2B mice. Scatter plots showing the distribution of place cells from control and L7-PP2B mice according to their S4–S5 similarity coefficient and S4–S5 rotation angle. Cells from unstable sessions are color-coded, emphasizing the angular coherence of cell ensembles. The few unstable cells observed in the controls come from sessions in which all other simultaneously recorded cells were stable. Error bars represent S.E.M.
Fig. 5
Fig. 5
L7-PP2B mice have higher high gamma power than controls upon reentry in the arena. a Raw traces from one L7-PP2B mice and one control mice during S1 and S2. b Average power spectrum normalized by total power in the 1–120 Hz frequency range computed over exploration epochs. c Barplots showing the normalized power of the theta (6–12 Hz, repeated measure ANOVA, genotype, F(1,8) =  1.24, p = 0.30; session, F(1,8) = 2.44, p = 0.16; genotype*session interaction, F(1,8) = 0.31, p = 0.59), low gamma (20–45 Hz, repeated measure ANOVA, genotype, F(1,8) = 1.96, p = 0.20; session, F(1,8) = 3.32, p = 0.10; session*genotype interaction F(1,8) = 3.70, p = 0.09) and high gamma (55–95 Hz, repeated measure ANOVA, genotype, F(1,8) = 5.3, p = 0.05; session, F(1,8) = 6.6, p = 0.03; session*genotype interaction F(1,8) = 6.1, p = 0.04; L7-PP2B, S1–S2, p = 0.007, controls-L7-PP2B in S2, p = 0.007, LSD post-hoc test) bands. *p < 0.05 with a LSD post-hoc test, error bars represent S.E.M. N = 5 independent mice for each control and L7-PP2B group
Fig. 6
Fig. 6
L7-PPB mice orientation abilities are impaired in the Morris Water Maze. a Performance of control (n = 12) and L7-PP2B (n = 10) mice improved significantly along the training sessions (repeated measure ANOVA, session F(4,20) = 16.6, p < 0.001; genotype, F(1,20) = 1.8, p = 0.19; session*genotype interaction, F(4,20) = 0.4, p = 0.83). b Distributions of traveled distances of all trials for control (gray) and L7-PP2B (black) mice. The bimodal distribution allowed the separation of direct and indirect trials using a Gaussian fit, the threshold is indicated by the red dashed line (p = 0.018 with a Fisher exact test). c Left, Top. Color-coded representation of traveled distances for all trials. Each line represents the performances of one mouse over the training. Bottom. Same representation with the categorization in successful (direct, blue) and failed (indirect, brown) trials. Right, The number of transitions between successful and failed trials is higher in L7-PP2B mice compared to controls (U = 22, p = 0.011, Mann–Whitney U-test) at the end of training (S4 and S5, indicated by the black frame on the left panel). d Mouse initial orientation is evaluated by the distance between mouse position and platform location after a 300 cm initial trajectory (repeated measure ANOVA genotype, F(1,20) = 5.6, p = 0.029; session, F(4,20) = 13.5, p < 0.001, session*genotype interaction, F(4,20) = 0.2, p = 0.92). The cartoon illustrates a trajectory in gray, the initial segment in black and the mouse–platform distance in blue. Inset: ANOVA p values for the same analysis performed for different lengths of initial trajectory segments showing that p < 0.05 from 200 to 600 cm lengths. e Left. Mean distance between the peak of exploration (corresponding to mouse search area) and the platform location (repeated measure ANOVA, genotype F(1,20) = 14.8, p = 0.001; session F(4,20) = 20.1 p < 0.001, genotype*session interaction, F(4,20) = 20.1, p = 0.54). The cartoon illustrates a map showing the platform (white circle), the peak of exploration (yellow), and the peak–platform distance (arrow). Right. Heat maps showing the spatial distribution of exploration peaks along the training. The cartoon indicates the platform location (black disk) in the pool (top left). See Supplementary Fig. 13 for a detailed description of the analyses. Error bars represent S.E.M.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. 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. doi: 10.1016/0006-8993(71)90358-1. - DOI - PubMed
    1. Leutgeb S, Leutgeb JK, Treves A, Moser MB, Moser EI. Distinct Ensemble codes in hippocampal areas CA3 and CA1. Science. 2004;305:1295–1298. doi: 10.1126/science.1100265. - DOI - PubMed
    1. Wills TJ, Lever C, Cacucci F, Burgess N, O’Keefe J. Attractor dynamics in the hippocampal representation of the local environment. Science. 2005;308:873–876. doi: 10.1126/science.1108905. - DOI - PMC - PubMed
    1. Leutgeb S, Leutgeb JK, Moser MB, Moser EI. Place cells, spatial maps and the population code for memory. Curr. Opin. Neurobiol. 2005;15:738–746. doi: 10.1016/j.conb.2005.10.002. - DOI - PubMed
    1. Kelemen E, Fenton A. Coordinating different representations in the hippocampus. Neurobiol. Learn. Mem. 2016;129:50–59. doi: 10.1016/j.nlm.2015.12.011. - DOI - PubMed

Publication types

LinkOut - more resources