Abstract

Schizophrenia is a severely debilitating neurodevelopmental disorder. Establishing a causal link between circuit dysfunction and particular behavioral traits that are relevant to schizophrenia is crucial to shed new light on the mechanisms underlying the pathology. We studied an animal model of the human 22q11 deletion syndrome, the mutation that represents the highest genetic risk of developing schizophrenia. We observed a desynchronization of hippocampal neuronal assemblies that resulted from parvalbumin interneuron hypoexcitability. Rescuing parvalbumin interneuron excitability with pharmacological or chemogenetic approaches was sufficient to restore wild-type-like CA1 network dynamics and hippocampal-dependent behavior during adulthood. In conclusion, our data provide insights into the network dysfunction underlying schizophrenia and highlight the use of reverse engineering to restore physiological and behavioral phenotypes in an animal model of neurodevelopmental disorder.

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The data that support the findings of this study are available from the corresponding authors upon reasonable request

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Acknowledgements

This paper is dedicated to the memory of D. Müller, whose ideas had inspired this study. He will continue to inspire all of us. We thank R. Kucherlapati (Harvard University) for generously providing the Lgdel/+ mice. We thank L. Jourdain and M.-P. Hervé for their technical support. We thank Y. Bernardelli, P. Mendez Garcia, T. Stefanelli, S. Eliez, P. Caroni, and other members of the NCCR SYNAPSY for helpful discussions and/or comments on the manuscript. This research was supported by the University of Geneva, the Swiss National Science Foundation (grant numbers: 31003A_172878 to A.C., 310030B_144080 to D.M. and 31003A_170114 to I.R.), the National Center of Competence in Research (NCCR) “SYNAPSY - The Synaptic Bases of Mental Diseases” financed by the Swiss National Science Foundation (grant 51NF40-158776, D.M. and A.C.), the Novartis Foundation for medical-biological research (grant 17A057 to A.C.) and the Lejeune Foundation (T.M.).

Author information

Author notes

    • Thomas Marissal

    Present address: Institut de Neurobiologie de la Méditerranée, UMR 1249 INSERM, Marseille, France

  1. These authors contributed equally to this work: Thomas Marissal, Rodrigo F. Salazar, Cristina Bertollini.

  2. Deceased: Dominique Müller.

Affiliations

  1. Department of Basic Neuroscience, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    • Thomas Marissal
    • , Rodrigo F. Salazar
    • , Cristina Bertollini
    • , Sophie Mutel
    • , Mathias De Roo
    • , Dominique Müller
    •  & Alan Carleton
  2. Department of Genetics and Evolution, Faculty of Sciences, University of Geneva, Geneva, Switzerland

    • Sophie Mutel
    •  & Ivan Rodriguez
  3. Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland

    • Mathias De Roo

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Contributions

T.M., D.M., and A.C. conceived the study. T.M., R.S., C.B., S.M., M.D.R., I.R., D.M., and A.C. contributed to the experimental design. TM performed the calcium imaging experiments and analyzed the data. C.B. carried out the in vitro electrophysiological experiments. R.S. performed the in vivo electrophysiological recordings and developed most of the MATLAB-based programs used for the analysis of the calcium imaging and the electrophysiological recordings. M.D.R. developed some MATLAB-based scripts used to analyze calcium-imaging data. T.M. and C.B. performed stereotaxic viral infections. T.M. performed behavioral experiments with the help of S.M. A.C., T.M., R.S., and I.R. wrote and edited the manuscript with comments from all of the other authors.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Thomas Marissal or Alan Carleton.

Integrated supplementary information

  1. Supplementary Figure 1 A subpopulation of neurons displays lower calcium transient frequency in Lgdel/+ mice when compared to WT mice.

    (a,b) Cumulative distributions of the frequency of calcium events recorded in Lgdel/+ and WT mice. The distributions are plotted either for every slice (a) or for the mean (± SEM, b). Statistical comparisons were done using two-way repeated measures ANOVA with two-sided Bonferroni post-hoc test (*P < 0.05: see Supplementary Table 1 for detailed statistics).

  2. Supplementary Figure 2 Representative example to illustrate the co-activation analysis of calcium transient onsets.

    (a,b) Raster plots of the calcium transient onsets for the actual data imaged in CA1 neurons of a representative WT slice. (c,d) Raster plots of the calcium transient onsets for the same dataset after one iteration of temporal shuffling (see methods, coactive neurons are indicated in cyan). (e,f) Ten thousands shuffling iterations were made and the iteration with the maximum number of co-activated cells at each frame was chosen as the threshold (magenta). All frames were considered as significant when the number of neurons in the actual data exceeded this threshold and were used to calculate the duration of the co-activations over the whole recordings. The numbers of active cells during these frames were considered as significant co-active neurons above chance (magenta).

  3. Supplementary Figure 3 Representative example to illustrate the cross-correlation analysis of paired cells.

    (a) Calcium traces of two neurons (blue and red) and identification of their calcium transient onsets. (b) The cross-correlation is presented as a histogram of the number of coincidences (shaded area) as a function of frame lags. A temporal shuffling procedure was used to estimate the significance threshold (dashed line, see methods). (c) Each time the number of coincidences exceeded the threshold, the corresponding frame lag (lower panel) was considered as significant. Data is shown for a few pairs of neurons.

  4. Supplementary Figure 4 Synaptic parameters recorded in PCs and PVIs from WT and Lgdel/+ mice.

    (a-d) Patch-clamp recordings of CA1 PCs from WT and Lgdel/+ mice. Summary graphs of the mean sEPSC (b) and mean sIPSC (c) amplitude. (d) Summary graph of the mean mEPSC IEI. (e-h) Patch-clamp recordings of CA1 PVIs from PvalbtdTom;+/+ and PvalbtdTom;Lgdel/+ mice. Summary graphs of the mean sEPSC (f) and mean sIPSC (g) amplitude. (h) Summary graph of the mean mEPSC IEI. All data are presented as mean ± SEM ; each circle represents a cell, number of cells indicated in parentheses; two-sided Mann-Whitney test were performed.

  5. Supplementary Figure 5 Effect of NRG1P application in vitro and in vivo on WT mice.

    (a-d) Network dynamics in slices from WT mice treated or not with NRG1P (data for not treated slices are the same as in Fig. 1). Percentage of co-active neurons above chance (a) and occurrence of these co-activations (b). (c) Percentage of correlated pairs of neurons above chance. (d) Distributions of significant time lags in correlated pairs (two-way repeated measures ANOVA, interaction genotype x time lags: F20,441 = 0.82, P = 0.69). The grey dashed line represents the equidistribution. Box: 25-75th percentiles, whiskers: 10-90th percentiles, white bar: median. (e,f) Distribution of the LFP PSDs in the theta band for WT mice before (same data as in Fig. 6a) and after NRG1P injection (PSDs averaged between 5 to 8 Hz in f, the number of shank/mouse pairs is indicated in parentheses). (g) Percentage of correlated neurons (median) in the CA1 region of awake mice as a function of time lags for WT animals before (same data as in Fig. 6d) and after NRG1P injection. The numbers of recorded animals are indicated in parentheses. (h) Distribution of central peaks of correlation curves (computed in ± 60 ms time window). (i-k) WT mice in the open field arena and during contextual fear conditioning after NRG1P administration. (i) Locomotor tracks during 10 min in an open field. (j) Distance travelled in the open field. (k) WT mice freezing behaviour in the control conditions and after treatments with NRG1P. All data are presented as mean ± SEM unless otherwise indicated. Each circle represents a mouse (total number of animal indicated in parentheses). (a-c,j,k): Two-sided Mann-Whitney test. (f,h): Two-sided Wilcoxon paired test.

  6. Supplementary Figure 6 Effects of PVI activation on various parameters in Lgdel/+ mice during calcium imaging.

    (a) Proportion of neurons displaying Ca2+ transients. (b) Frequency (c), amplitude (c) and duration (d) of Ca2+ transients recorded in CA1 neurons. (e) Percentage of co-active neurons above random co-activation. (f) Occurrences of the co-activations. Statistical comparisons were done with two-sided Mann-Whitney test. Data are presented as mean ± SEM (number of slices in indicated in parentheses).

  7. Supplementary Figure 7 In vivo local field potential recordings using polytrodes and DREADD infection in the hippocampus.

    (a) Photograph of the track resulting from the implantation in the dorsal CA1 (dCA1) of the silicon probes coated with DiI. For each shank, the recording sites close the CA1 layer were used for LFP spectral analysis (see methods). (b) Distributions of LFP power spectra for WT and Lgdel/+ (mean ± SEM; number in parentheses indicate the numbers of mouse/shank pairs). (c) Photographs showing the AAV-mediated expression of hM3Gq-tdTomato in dCA1 PVI from two different mice (experiment was repeated independently 12 times with similar results, see Figs. 6,7 for effects on physiology and behavior).

  8. Supplementary Figure 8 Power spectral densities of local field potentials (LFP) in the delta and gamma frequency ranges.

    (a,b) Distribution of the LFP PSDs in the delta and gamma frequency ranges for WT (+/+) and Lgdel/+ mice (two-sided Mann-Whitney test; mean ± SEM; number in parentheses indicate the number of shank/mouse pairs). Data from Lgdel/+ and Pvalbcre/+;Lgdel/+ during the baseline were grouped and referred as Lgdel/+ control mice (all ctrl Lgdel/+). (c) PSDs in the gamma frequency range in WT and Lgdel/+ mice in the control conditions or after treatments with NRG1P or CNO (two-sided Wilcoxon paired test; mean ± SEM; number in parentheses indicate the number of shank/mouse pairs).

  9. Supplementary Figure 9 Effect of increasing PVI excitability on mouse behaviour.

    (a) Averaged startle response to a 120 dB tone in two representative mice (a.u. arbitrary unit). (b) Summary graph of the startle response. Statistical comparisons were done with two-sided Mann-Whitney test except for the chemogenetic manipulation where we used a two-sided Wilcoxon paired test. (c) Summary graph of the pre-pulse inhibition of the acoustic startle reflex. Statistical comparisons were done with two-way repeated measures ANOVA (number of animals indicated in parentheses). Data presented as box plots (box: 25-75th percentiles, whiskers: 10-90th percentiles, white bar: median). (d) Mice freezing behaviour in the different conditions during the fear conditioning (two-sided Mann-Whitney or two-sided Wilcoxon paired test for genotype comparison or drug treatments, respectively). All data are presented as mean ± SEM. Each circle represents a mouse (total number of animals indicated in parentheses).

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–9

  2. Reporting Summary

  3. Supplementary Table 1

    Statistics summary table. Details about all statistical tests presented in the study.

  4. Supplementary Video 1

    Population dynamics in a WT slice. Supplementary video showing the neuronal co-activations during calcium imaging of a hippocampal slice culture (treated with Carbachol) originating from a WT mouse. (experiment was repeated 14 times independently with similar results, see Fig. 1e-h for quantifications).

  5. Supplementary Video 2

    Population dynamics in a Lgdel/+ slice. Supplementary video showing the neuronal co-activations during calcium imaging of a hippocampal slice culture (treated with Carbachol) originating from a Lgdel/+ mouse (experiment was repeated 22 times independently with similar results, see Fig. 1e-h for quantifications).

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https://doi.org/10.1038/s41593-018-0225-y