Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Altered hippocampal replay is associated with memory impairment in mice heterozygous for the Scn2a gene

Nature Neuroscience volume 21, pages 996–1003 (2018)Cite this article

Subjects

Abstract

An accumulating body of experimental evidence has implicated hippocampal replay occurring within sharp wave ripples (SPW-Rs) as crucial for learning and memory in healthy subjects. This raises speculation that neurological disorders impairing memory disrupt either SPW-Rs or their underlying neuronal activity. We report that mice heterozygous for the gene Scn2a, a site of frequent de novo mutations in humans with intellectual disability, displayed impaired spatial memory. While we observed no changes during encoding, to either single place cells or cell assemblies, we identified abnormalities restricted to SPW-R episodes that manifest as decreased cell assembly reactivation strengths and truncated hippocampal replay sequences. Our results suggest that alterations to hippocampal replay content may underlie disease-associated memory deficits.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Spatial encoding is unaltered despite deficits in spatial working memory task performance.
Fig. 2: Altered CA1 place cell activity during SPW-R episodes.
Fig. 3: Altered CA1 cell assembly properties in Scn2a+/− mice.
Fig. 4: Replayed trajectory sequences are truncated in Scn2a+/− mice.

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. 34, 171–175 (1971).

    Article  PubMed  Google Scholar 

  2. Jones, M. W. & Wilson, M. A. Theta rhythms coordinate hippocampal-prefrontal interactions in a spatial memory task. PLoS Biol. 3, e402 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Foster, D. J. & Wilson, M. A. Hippocampal theta sequences. Hippocampus 17, 1093–1099 (2007).

    Article  PubMed  Google Scholar 

  4. Middleton, S. J. & McHugh, T. J. Silencing CA3 disrupts temporal coding in the CA1 ensemble. Nat. Neurosci. 19, 945–951 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Pfeiffer, B. E. & Foster, D. J. Hippocampal place-cell sequences depict future paths to remembered goals. Nature 497, 74–79 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Diba, K. & Buzsáki, G. Forward and reverse hippocampal place-cell sequences during ripples. Nat. Neurosci. 10, 1241–1242 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Skaggs, W. E. & McNaughton, B. L. Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience. Science 271, 1870–1873 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Harris, K. D., Csicsvari, J., Hirase, H., Dragoi, G. & Buzsáki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. van de Ven, G. M., Trouche, S., McNamara, C. G., Allen, K. & Dupret, D. Hippocampal offline reactivation consolidates recently formed cell assembly patterns during sharp wave-ripples. Neuron 92, 968–974 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Girardeau, G., Benchenane, K., Wiener, S. I., Buzsáki, G. & Zugaro, M. B. Selective suppression of hippocampal ripples impairs spatial memory. Nat. Neurosci. 12, 1222–1223 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Ego-Stengel, V. & Wilson, M. A. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat. Hippocampus 20, 1–10 (2010).

    PubMed  PubMed Central  Google Scholar 

  12. Jadhav, S. P., Kemere, C., German, P. W. & Frank, L. M. Awake hippocampal sharp-wave ripples support spatial memory. Science 336, 1454–1458 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cayzac, S. et al. Altered hippocampal information coding and network synchrony in APP-PS1 mice. Neurobiol. Aging 36, 3200–3213 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Gillespie, A. K. et al. Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples. Neuron 90, 740–751 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nicole, O. et al. Soluble amyloid beta oligomers block the learning-induced increase in hippocampal sharp wave-ripple rate and impair spatial memory formation. Sci. Rep. 6, 22728 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Planells-Cases, R. et al. Neuronal death and perinatal lethality in voltage-gated sodium channel αII-deficient mice. Biophys. J. 78, 2878–2891 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sugawara, T. et al. A missense mutation of the Na+ channel αII subunit gene Na v1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc. Natl. Acad. Sci. USA 98, 6384–6389 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kamiya, K. et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J. Neurosci. 24, 2690–2698 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rauch, A. et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Carroll, L. S. et al. Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation. Psychiatr. Genet. 26, 60–65 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ogiwara, I. et al. De novo mutations of voltage-gated sodium channel αII gene SCN2A in intractable epilepsies. Neurology 73, 1046–1053 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamamoto, J., Suh, J., Takeuchi, D. & Tonegawa, S. Successful execution of working memory linked to synchronized high-frequency gamma oscillations. Cell 157, 845–857 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Osipova, D. et al. Theta and gamma oscillations predict encoding and retrieval of declarative memory. J. Neurosci. 26, 7523–7531 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Montgomery, S. M., Sirota, A. & Buzsáki, G. Theta and gamma coordination of hippocampal networks during waking and rapid eye movement sleep. J. Neurosci. 28, 6731–6741 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wilson, M. A. & McNaughton, B. L. Reactivation of hippocampal ensemble memories during sleep. Science 265, 676–679 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Ambrose, R. E., Pfeiffer, B. E. & Foster, D. J. Reverse replay of hippocampal place cells is uniquely modulated by changing reward. Neuron 91, 1124–1136 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Grosmark, A. D. & Buzsáki, G. Diversity in neural firing dynamics supports both rigid and learned hippocampal sequences. Science 351, 1440–1443 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Suh, J., Foster, D. J., Davoudi, H., Wilson, M. A. & Tonegawa, S. Impaired hippocampal ripple-associated replay in a mouse model of schizophrenia. Neuron 80, 484–493 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Tang, W., Shin, J. D., Frank, L. M. & Jadhav, S. P. Hippocampal-prefrontal reactivation during learning is stronger in awake compared with sleep states. J. Neurosci. 37, 11789–11805 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Carr, M. F., Karlsson, M. P. & Frank, L. M. Transient slow gamma synchrony underlies hippocampal memory replay. Neuron 75, 700–713 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Witton, J. et al. Disrupted hippocampal sharp-wave ripple-associated spike dynamics in a transgenic mouse model of dementia. J. Physiol. (Lond.) 594, 4615–4630 (2016).

    Article  CAS  Google Scholar 

  35. Davidson, T. J., Kloosterman, F. & Wilson, M. A. Hippocampal replay of extended experience. Neuron 63, 497–507 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stark, E. et al. Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations. Neuron 83, 467–480 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Foster, D. J. Replay comes of age. Annu. Rev. Neurosci. 40, 581–602 (2017).

    Article  CAS  PubMed  Google Scholar 

  38. Roux, L., Hu, B., Eichler, R., Stark, E. & Buzsáki, G. Sharp wave ripples during learning stabilize the hippocampal spatial map. Nat. Neurosci. 20, 845–853 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schomburg, E. W. et al. Theta phase segregation of input-specific gamma patterns in entorhinal-hippocampal networks. Neuron 84, 470–485 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. English, D. F. et al. Excitation and inhibition compete to control spiking during hippocampal ripples: intracellular study in behaving mice. J. Neurosci. 34, 16509–16517 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gan, J., Weng, S. M., Pernía-Andrade, A. J., Csicsvari, J. & Jonas, P. Phase-locked inhibition, but not excitation, underlies hippocampal ripple oscillations in awake mice in vivo. Neuron 93, 308–314 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Buzsáki, G. Hippocampal sharp wave-ripple: a cognitive biomarker for episodic memory and planning. Hippocampus 25, 1073–1188 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Sullivan, D. et al. Relationships between hippocampal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical activity. J. Neurosci. 31, 8605–8616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cabral, H. O. et al. Oscillatory dynamics and place field maps reflect hippocampal ensemble processing of sequence and place memory under NMDA receptor control. Neuron 81, 402–415 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Schmitzer-Torbert, N., Jackson, J., Henze, D., Harris, K. & Redish, A. D. Quantitative measures of cluster quality for use in extracellular recordings. Neuroscience 131, 1–11 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. McHugh, T. J., Blum, K. I., Tsien, J. Z., Tonegawa, S. & Wilson, M. A. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Cell 87, 1339–1349 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Varga, C., Golshani, P. & Soltesz, I. Frequency-invariant temporal ordering of interneuronal discharges during hippocampal oscillations in awake mice. Proc. Natl. Acad. Sci. USA 109, E2726–E2734 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fernandez-Ruiz, A. et al. Entorhinal-CA3 dual-input control of spike timing in the hippocampus by theta-gamma coupling. Neuron 93, 1213–1226.e1215 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Berens, P. CircStat: a MATLAB toolbox for circular statistics. J. Stat. Softw. 31, https://doi.org/10.18637/jss.v031.i10 (2009).

  50. Skaggs, W. E., McNaughton, B. L., Wilson, M. A. & Barnes, C. A. Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus 6, 149–172 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Mizuseki, K., Sirota, A., Pastalkova, E. & Buzsáki, G. Theta oscillations provide temporal windows for local circuit computation in the entorhinal-hippocampal loop. Neuron 64, 267–280 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Trouche, S. et al. Recoding a cocaine-place memory engram to a neutral engram in the hippocampus. Nat. Neurosci. 19, 564–567 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Peyrache, A., Benchenane, K., Khamassi, M., Wiener, S. I. & Battaglia, F. P. Principal component analysis of ensemble recordings reveals cell assemblies at high temporal resolution. J. Comput. Neurosci. 29, 309–325 (2010).

    Article  PubMed  Google Scholar 

  54. Marchini, J. L., Heaton, C. & Ripley, B. D. FastICA: fastICA algorithms to perform ICA and projection pursuit. https://CRAN.R-project.org/package=fastICA (2013).

  55. McNamara, C. G., Tejero-Cantero, Á., Trouche, S., Campo-Urriza, N. & Dupret, D. Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence. Nat. Neurosci. 17, 1658–1660 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Silva, D., Feng, T. & Foster, D. J. Trajectory events across hippocampal place cells require previous experience. Nat. Neurosci. 18, 1772–1779 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all members of the CBP laboratory for their support and the RIKEN Advanced Manufacturing Team for their assistance in microdrive production. This work was supported by NIH grant GM49711 (M.M.), JSPS Kakenhi 26750378 (S.J.M.), JSPS Kakenhi 21791020 and MEXT 25461572 (I.O.), JSPS Kakenhi 17H05986 (T.J.M), SRPBS from MEXT and AMED (K.Y.) and RIKEN BSI (K.Y. and T.J.M.).

Author information

Authors and Affiliations

  1. Laboratory for Circuit and Behavioral Physiology, RIKEN Brain Science Institute, Wakoshi, Saitama, Japan

    Steven J. Middleton, Emily M. Kneller, Shuo Chen & Thomas J. McHugh

  2. RIKEN Center for Brain Science, Wakoshi, Saitama, Japan

    Steven J. Middleton, Shuo Chen, Kazuhiro Yamakawa & Thomas J. McHugh

  3. Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wakoshi, Saitama, Japan

    Ikuo Ogiwara & Kazuhiro Yamakawa

  4. Department of Physiology, Nippon Medical School, Tokyo, Japan

    Ikuo Ogiwara

  5. Section of Neurobiology, University of California San Diego, California, La Jolla, USA

    Mauricio Montal

  6. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan

    Thomas J. McHugh

Authors
  1. Steven J. Middleton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emily M. Kneller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ikuo Ogiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mauricio Montal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuhiro Yamakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thomas J. McHugh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.J.M, T.J.M. and K.Y. conceived the study. I.O. performed Barnes maze experiments. S.J.M. and E.M.K. performed all other experiments. S.J.M. and S.C. analyzed the data. M.M. created the transgenic mouse. S.J.M. and T.J.M. wrote the manuscript. Lead contact T.J.M.

Corresponding authors

Correspondence to Steven J. Middleton, Kazuhiro Yamakawa or Thomas J. McHugh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Integrated Supplementary Information

Supplementary Figure 1 Spatial learning, place fields and tetrode locations.

(a) Latencies during Barnes maze learning over a four day period revealed control mice (blue) learned faster than Scn2a+/- mice (red) (P = 0.0027, F = 5.19, 2-way repeated measures ANOVA, followed by post-hoc Bonferroni test P<0.01 on day 3; CTR: N = 14 animals; SCN: N = 14 animals). (b) The spatial receptive fields are shown for all recorded place cells during linear track exploration sessions. Individual grey lines represent single place cell rate maps across the entirety of the track, dark red areas indicate place fields determined as described in the methods section. Control (left) and Scn2a+/- (right) fields are ordered according to their peak position on the track. (c) Reconstructed tetrode tip locations from three animals of each genotype (blue CTR, pink Scn2a+/-) overlaid onto schematic mouse brain slices, numbers indicate posterior distances from bregma. Tetrodes circled in red were excluded as they were either poorly targeted or were devoid of place cells. All boxplots represent the median (black line) and the 25th-75th percentiles, with whiskers extending to the most extreme data points, excluding outliers which are plotted as individual crosses. *P < 0.05.

Supplementary Figure 2 Sharp wave ripple event detection.

(a) Upper traces (WB) show five examples of raw CA1 stratum pyramidale local field potentials recorded from control mice during a rest period in a small sleep box. Blue traces represent activity centered on events detected as SPW-Rs, with the period detected as a ripple (as described in the methods section) highlighted in red. Below these are the same LFPs band-pass filtered between 80–200 Hz. The bottom panel shows multi-unit activity of all clustered place cells for the corresponding time periods. (b) Shows the same but for Scn2a+/- mice. Scale bars represent 100 ms (horizontal) and 100 µV (vertical) throughout.

Supplementary Figure 3 Detection of cell assemblies.

(a) Session example showing assembly spatial maps (of 12 cell assemblies) ordered from left to right across the entirety of the linear track. (b) Corresponding data showing the 57 CA1 place cells recorded during this session, each neurons weight in a given assembly is indicated by its deviation on the x-axis. Cells with a significant weight are color coded to the assembly to which they belong (from a). (c) Mean assembly strength during linear track exploration did not differ between genotypes (P = 0.83, Z = 0.22, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 96 cell assemblies; SCN: N = 7 animals, n = 132 cell assemblies). (d) Cells classified as forming part of an assembly had significantly higher co-firing coefficients (r) with assembly partners, than cells which did not form part of any assembly (P = 3.32 × 10−23, Z = 9.92, two-sided Wilcoxon Rank-sum; n = 59 assembly cell pairs, n = 105 non-assembly cell pairs), relating to example session shown in a & b. (e) Place-field similarity was also significantly greater for assembly member pairs, compared with non-members (P = 1.62 × 10−16, Z = 8.25, two-sided Wilcoxon Rank-sum; n = 59 assembly cell pairs, n = 105 non-assembly cell pairs). (f) Across all subjects during SPW-Rs, cell pairs forming part of an assembly had consistently higher co-firing coefficients independent of genotype (CTRs, P = 1.28 × 10−52, Z = 15.3, two-sided Wilcoxon Rank-sum; SCN, P = 7.82 × 10−67, Z = 17.3, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals; SCN: N = 7 animals), when compared to non-members. (g) Place field similarity was also significantly higher for cell-assembly members for both controls (P = 1.25 × 10−21, Z = 9.55, two-sided Wilcoxon Rank-sum, N = 7 animals) and mutants (P = 4.31 × 10−25, Z = 10.3, two-sided Wilcoxon Rank-sum, N = 7 animals). Cell-assembly members (P = 0.31, Z = 1.02, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals; SCN: N = 7 animals) and non-members (P = 0.73, Z = 0.35, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals; SCN: N = 7 animals) were not significantly different when compared across genotype. All boxplots represent the median (black line) and the 25th-75th percentiles, with whiskers extending to the most extreme data points, excluding outliers which are plotted as individual crosses. *P < 0.05.

Supplementary Figure 4 Spike waveforms and Bayesian decoding of position.

(a) Left panel shows decoding accuracy for a full linear track exploration session, with hot colors indicating highest probabilities and high probabilities along the diagonal demonstrating decoded positions accurately reflect the real world positon of the animal. Middle panel shows multiple traversals of the linear track using the Bayesian decoder, hot colors representing highest probability, red line indicates true position and is shifted vertically for clarity. Right panel shows the mean decoding error for both control (blue) and Scn2a+/- mice (red), with individual points representing single animals (P = 0.99, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals; SCN: N = 7 animals). (b) Example spike waveforms recorded from control mice in CA1 stratum pyramidale, for both neurons classified as both pyramidal cells (top left) and parvalbumin-like interneurons (top right). Middle panel (blue) shows average waveforms for all pyramidal (left) and PV-like (right) neurons from control mice. Scn2a+/- average waveforms are shown in the bottom panel (red) with pyramidal left and PV-like to the right, shaded areas represent SEM. (c) Pyramidal (blue) and PV-like neurons (red) were separable into two distinct clusters based on waveform asymmetry and firing frequency, however within cell types, genotypes (control and Scn2a+/- are represented by dark and light colors respectively) were indistinguishable. (d) Example phase precession plots for three place cells from each genotype (control and Scn2a+/- in blue and red respectively), showing spikes moving to progressively earlier phases with increasing passage into place fields. (e) Histograms showing the relative frequency of all place cells relative to LFP theta, with positive values indicate phase precession of cells (P = 0.24, Z = 1.16, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 224 cells; SCN: N = 7 animals, n = 274 cells). All boxplots represent the median (black line) and the 25th-75th percentiles, with whiskers extending to the most extreme data points, excluding outliers which are plotted as individual crosses. *P < 0.05.

Supplementary Figure 5 Awake replay events are truncated in a similar manner to sleep replays.

(a) Cumulative distribution of sequence scores (rZ) for events detected by both MUA and ripple power, the means ± SEM are displayed in the inset (P = 0.33, Z = 0.98, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 241 events; SCN: N = 7 animals, n = 255 events). (b) Group data showing mean distances spanned by replay events detected by a combination of both MUA and ripple power (P = 2.4 × 10−5, Z = 4.23, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 241 events; SCN: N = 7 animals, n = 255 events). (c) Average speed in m/s of progression from starting position to end position for all replay events detected by MUA and ripple power (P = 4.1 × 10−4, Z = 3.5, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 241 events; SCN: N = 7 animals, n = 255 events). (d) The average spatial jump in centimeters for decoded positons in adjacent temporal bins, for each replay event (P = 0.016, Z = 2.41, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 241 events; SCN: N = 7 animals, n = 255 events). (e) Mean z-scored LFP ripple power concurrent with all significant replay events, lined up to the time of initial detection of the events (CTR: N = 7 animals, n = 241 events; SCN: N = 7 animals, n = 255 events), control (blue) and Scn2a+/- (red) are represented by their respective colors throughout (a–e). (f) Examples of trajectory sequences derived from Bayesian decoding of spiking activity during awake SPW-Rs, top row represents controls, beneath are Scn2a+/- examples. (g) Representative examples of unfiltered SPW-Rs during the awake exploratory session, for both control (blue) and Scn2a+/- (red). (h) Mean replay event sequence scores (rZ) for control (blue) and Scn2a+/- (red) in the awake exploratory session (P = 0.97, Z = 0.03, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 59 events; SCN: N = 7 animals, n = 88 events). (i) Group data showing mean distances spanned by awake replay events detected by a combination of both MUA and ripple power (P = 0.044, Z = 2.0, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 59 events; SCN: N = 7 animals, n = 88 events). (j) Average speed in m/s of progression from starting position to end position for all awake replay events detected by MUA and ripple power (P = 0.027, Z = 2.2, two-sided Wilcoxon Rank-sum; CTR: N = 7 animals, n = 59 events; SCN: N = 7 animals, n = 88 events). (k) Mean z-scored LFP ripple power concurrent with all significant awake replay events, lined up to the time of initial detection (combined ripple power and MUA), control and Scn2a+/- are represented by blue and red respectively (CTR: N = 7 animals, n = 59 events; SCN: N = 7 animals, n = 88 events). All boxplots represent the median (black line) and the 25th–75th percentiles, with whiskers extending to the most extreme data points, excluding outliers which are plotted as individual crosses. *P < 0.05.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Table 1

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Middleton, S.J., Kneller, E.M., Chen, S. et al. Altered hippocampal replay is associated with memory impairment in mice heterozygous for the Scn2a gene. Nat Neurosci 21, 996–1003 (2018). https://doi.org/10.1038/s41593-018-0163-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-018-0163-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing