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Cellular origins of auditory event-related potential deficits in Rett syndrome

Abstract

Dysfunction in sensory information processing is a hallmark of many neurological disorders, including autism spectrum disorders, schizophrenia and Rett syndrome (RTT). Using mouse models of RTT, a monogenic disorder caused by mutations in MECP2, we found that the large-scale loss of MeCP2 from forebrain GABAergic interneurons led to deficits in auditory event-related potentials and seizure manifestation, whereas the restoration of MeCP2 in specific classes of interneurons ameliorated these deficits.

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Figure 1: MeCP2 function in forebrain GABAergic, but not glutamatergic neurons, is necessary for auditory ERPs.
Figure 2: Preservation of MeCP2 function in forebrain GABAergic neurons restores auditory ERPs in Mecp2-null mice.
Figure 3: Preservation of MeCP2 function in either SOM- or PV-expressing interneurons leads to a partial restoration of auditory ERPs.

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Acknowledgements

We thank members of the Zhou laboratory for critical reading of the manuscript. This work was supported by US National Institutes of Health grants R01 NS081054 and R01 MH091850 (Z.Z.) and the International Rett Syndrome Foundation (Z.Z. and D.G.). Z.Z. is a Pew Scholar in Biomedical Sciences.

Author information

Authors and Affiliations

Authors

Contributions

D.G. and Z.Z. designed the experiments and wrote the manuscript. D.G. conducted the experiments and performed data analysis. E.S.B. and J.A.B. helped to design and interpret the behavioral tests. S.J.S. helped to design and interpret the electrophysiology studies.

Corresponding author

Correspondence to Zhaolan Zhou.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Auditory evoked phase-locking factor (PLF) responses following loss of MeCP2 from forebrain GABAergic or glutamatergic neurons.

a) Heat maps showing changes in event-related PLF in response to 85-dB white noise sound presentation as a function of time and frequency. (b) Population averages of event-related power separated into frequency bands (δ, 2-4 Hz; θ, 4-8 Hz; α, 8-12 Hz; β, 12-30 Hz; γlow, 30-50 Hz; γhigh, 50-90 Hz; ɛ, 90-140 Hz) for Mecp22lox/y; Dlx5/6-Cre mice (n = 13) and their wild-type (Mecp22lox/y) littermates (n = 9). (c) Population averages for Mecp22lox/y; Emx1-Cre mice (n = 7) and their Mecp22lox/y littermates (n = 7). Shaded regions represent s.e.m. Top blue bars represent those regions with an FDR < 0.05 (permutation test).

Supplementary Figure 2 Auditory brainstem responses are not affected following deletion of MeCP2 from forebrain GABAergic or glutamatergic neurons.

Auditory brain stem responses (ABR) from Mecp22lox/y, Mecp22lox/y; Emx1-Cre and Mecp22lox/y; Dlx5/6-Cre mice. ABR responses decreased to a similar extent in all three genotypes with decreasing sound pressure.

Supplementary Figure 3 Elevated high frequency oscillations following conditional deletion of MeCP2 from forebrain GABAergic or glutamatergic neurons.

Basal EEG power measurements in Mecp22lox/y; Dlx5/6-Cre mice (n = 13), Mecp22lox/y; Emx1-Cre mice (n = 7) mice and their wild-type (Mecp22lox/y) littermates (n = 9). Insets show 40-80 Hz mean amplitudes across EEG recordings. Scale bars represent one oscillation cycle (horizontal) and 20 μV (vertical). Bars represent mean ± s.e.m. *P < 0.05, two–tailed t-test with Bonferroni correction.

Supplementary Figure 4 Event-related power or PLF are not affected by loss of MeCP2 from D1 - or D2-dopamine receptor-expressing medium spiny neurons.

Heat maps showing changes in event-related power (a) or PLF (b) in response to 85-dB white noise sound presentation as a function of time and frequency in Mecp22lox/y; D1-Cre mice (n = 9), Mecp22lox/y; D2-Cre mice (n = 10) and wild-type (Mecp22lox/y) littermates (n = 9).

Supplementary Figure 5 Behavioral analysis of mice lacking MeCP2 in forebrain glutamatergic neurons.

(a) Percentage time spent in open and closed regions of elevated zero maze (p = 0.50). (b) Number of beam breaks across 5 minutes of open field assay (p = 0.043). (c) Percentage time spent in center and periphery of open field assay (p = 0.50). (d) Latency to fall from accelerating rotarod (F[1, 272] = 3.70, p = 0.056, genotype). (e) Social approach towards a social (mouse) versus a nonsocial object in a three-chamber test (F[1, 14] = 0.02, p = 0.89, genotype). (f) Social approach behavior towards a novel mouse versus a familiar cage mate control mouse in a three-chamber test (F[1, 12] = 0.78, p = 0.40, genotype). (g) Time spent freezing during fear-conditioning training following foot shocks (F[1, 51] = 1.57, p = 0.22, genotype). (h) Time spent freezing in response to context or cue 24 hours following training (F[1, 34] = 3.11, p = 0.09, genotype). Bars represent mean ± s.e.m. Statistics were performed using two-way ANOVA or an unpaired two-tailed t-test with Welch's correction. Behavioral experiments were performed at 13-15 weeks of age (n = 9 for Mecp22lox/y; Emx1-Cre mice and n = 10 for wild-type, Mecp22lox/y littermates).

Supplementary Figure 6 Preservation of MeCP2 expression in GAD67- and PV-expressing interneurons in Mecp2Stop/y; Dlx5/6-Cre but not Mecp2Stop/y; Emx1-Cre mice.

Representative images showing MeCP2 expression in cortex and its co-localization with GAD67 (a) or Parvalbumin (b). Scale bars correspond to 75 μm. MeCP2 immunoreactivity is absent from GAD67- and PV-expressing neurons in Mecp2Stop/y; Emx1-Cre mice. In contrast, MeCP2 expression is preserved in GAD67-and PV-expressing neurons in Mecp2Stop/y; Dlx5/6-Cre mice. These localization patterns were observed in three mice per genotype.

Supplementary Figure 7 Amelioration of PLF deficits following preservation of MeCP2 expression in forebrain GABAergic but not glutamatergic neurons.

(a) Heat maps showing changes in event-related PLF in response to 85-dB white noise sound presentation as a function of time and frequency. (b) Population averages of event-related power separated into frequency bands (δ, 2-4 Hz; θ, 4-8 Hz; α, 8-12 Hz; β, 12-30 Hz; γlow, 30-50 Hz; γhigh, 50-90 Hz; ɛ, 90-140 Hz) for Mecp2Stop/y; Dlx5/6-Cre mice (n = 11), Mecp2Stop/y; Emx1-Cre mice (n = 6), Mecp2Stop/y mice (n = 9) and WT littermates (n = 9). Shaded regions represent s.e.m. Top blue bars represent those regions with an FDR < 0.05 (permutation test).

Supplementary Figure 8 Overt RTT-like phenotypes and premature lethality are not ameliorated by preservation of MeCP2 expression in forebrain GABAergic or glutamatergic neurons.

(a) Phenotypic scoring of RTT-like phenotypes in mice at 12 weeks of age (n = 7 per genotype). Statistics performed using one-way ANOVA with Tukey post-test analysis (F(2,18) = 0.13, p = 0.88, genotype). (b) Longevity of mice with indicated genotypes (n = 7 per genotype).

Supplementary Figure 9 Event-related power or PLF are not affected by loss of MeCP2 from PV- or SOM-expressing interneurons.

Heat maps showing changes in event-related power (a) or PLF (b) in response to 85-dB white noise sound presentation as a function of time and frequency in Mecp22lox/y; Sst-Cre mice (n = 14), Mecp22lox/y; Pvalb-Cre mice (n = 10) and wild-type Mecp22lox/y littermates (n = 12).

Supplementary Figure 10 Amelioration of PLF deficits following preservation of MeCP2 expression in PV- or SOM-expressing interneurons.

(a) Heat maps showing changes in event-related PLF in response to 85-dB white noise sound presentation as a function of time and frequency. (b) Population averages of event-related power separated into frequency bands (δ, 2-4 Hz; θ, 4-8 Hz; α, 8-12 Hz; β, 12-30 Hz; γlow, 30-50 Hz; γhigh, 50-90 Hz; ɛ, 90-140 Hz) for Mecp2Stop/y; Pvalb-Cre mice (n = 7) and Mecp2Stop/y mice (n = 9). (c) Population averages for Mecp2Stop/y; Sst-Cre (n = 12) and Mecp2Stop/y mice (n = 9). Shaded regions represent s.e.m. Top line represents those regions with an FDR < 0.05 (permutation test).

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 4280 kb)

Supplementary Methods Checklist (PDF 390 kb)

Supplementary Video 1

A behavioral seizure observed in an Mecp22lox/y; Dlx5/6-Cre mouse. (MOV 8033 kb)

Supplementary Video 2

A behavioral seizure observed in another Mecp22lox/y; Dlx5/6-Cre mouse. (MOV 15177 kb)

Supplementary Video 3

A seizure leading to bubbling liquid at mouth in an Mecp22lox/y; Dlx5/6-Cre mouse. (MOV 26695 kb)

Supplementary Video 4

A behavioral seizure observed in an Mecp2Stop/y; Emx1-Cre mouse. (MOV 12042 kb)

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Goffin, D., Brodkin, E., Blendy, J. et al. Cellular origins of auditory event-related potential deficits in Rett syndrome. Nat Neurosci 17, 804–806 (2014). https://doi.org/10.1038/nn.3710

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