Abstract
Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life before experiencing profound motor and cognitive decline1,2,3. At present there are no effective treatments for Rett syndrome, but we hypothesized that using the period of normal development to strengthen motor and memory skills might confer some benefit. Here we find, using a mouse model of Rett syndrome, that intensive training beginning in the presymptomatic period dramatically improves the performance of specific motor and memory tasks, and significantly delays the onset of symptoms. These benefits are not observed when the training begins after symptom onset. Markers of neuronal activity and chemogenetic manipulation reveal that task-specific neurons that are repeatedly activated during training develop more dendritic arbors and have better neurophysiological responses than those in untrained animals, thereby enhancing their functionality and delaying symptom onset. These results provide a rationale for genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset. Similar strategies should be studied for other childhood neurological disorders.
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Data availability
Data generated during this study are available from the corresponding author on reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank the Neurovisualization and Neurobehavioral Cores at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (BCM-IDDRC) (US National Institutes of Health (NIH) grant 5P50HD103555). This project was supported by NIH/National Institutes of Neurological Disorders and Stroke (NINDS) grant 5R01NS057819-13 (to H.Y.Z.), NIH/National Institute of Child Health and Human Development (NICHD) F30HD097871-01 (to N.P.A.), and the Henry Engel Fund. We thank the Baylor College of Medicine Center for Comparative Medicine for management of mouse colonies; S. Veeraragavan for assistance with mouse behaviour; D. Yu for microscopy assistance; and the Baylor College of Medicine Gene Vector core for production of AAVs. We thank members of the Zoghbi laboratory for discussions and comments on the manuscript, and V. Brandt and C. Alcott for helpful editorial input. Figure diagrams were created with BioRender.com.
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N.P.A. and H.Y.Z designed the experiments and interpreted the data. N.P.A and W.W. performed the experiments and analysed the data. N.P.A and H.Y.Z wrote and edited the manuscript.
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Extended data figures and tables
Extended Data Fig. 1 Presymptomatic motor training on the rotarod does not mitigate other behavioural deficits in Rett mice.
a, Motor performance on the rotarod. Eight-week-old wild-type (WT; n = 12) and Rett (n = 10) mice were tested over four days. b, Timeline for additional behavioural assays in rotarod-trained mice. c, Performance curves of rotarod-trained Rett naive (n = 19), late-trained (n = 18) and early-trained (n = 19) mice across training and test days. d–o, After rotarod testing at 24 weeks of age, WT naive (n = 12), Rett naive (n = 12), WT late-trained (n = 12), Rett late-trained (n = 11), WT early-trained (n = 11) and Rett early-trained (n = 12) mice were tested on a variety of behavioural assays. d, e, Motor function was tested in the footslip (d) and open-field assays (e). f–h, Spatial memory was tested in the Morris water maze. i, Social behaviour was tested in the three-chamber assay. j, Anxiety was tested in the elevated plus maze. k, l, Sensorimotor gating was tested in the acoustic startle (k) and prepulse inhibition assays (l). m, n, Contextual (m) and cued (n) memory were assessed in assays of fear conditioning. o, Body weight was measured. The sample size (n) corresponds to the number of biologically independent mice. Data are represented as means ± s.e.m. Statistical significance was determined using a two-way ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05; ****P < 0.0001.
Extended Data Fig. 2 Presymptomatic memory training in the Morris water maze does not mitigate other behavioural deficits in Rett mice.
a–c, Spatial memory performance in the Morris water maze. a, WT (n = 8) and Rett (n = 8) mice were tested over four days beginning at four weeks of age. b, c, A probe trial on day 5 revealed the time spent in the target quadrant (b) and the number of crossings of the platform area (c). d, Performance curves of mice trained in or naive to the Morris water maze—Rett naive (n = 19), late-trained (n = 19) and early-trained (n = 18) mice—across training and test days. e, Spatial memory in the Morris water maze over time in early-trained Rett mice (n = 7) and Rett mice that missed a training session (n = 8). f, Swim speed in the Morris water maze of WT naive (n = 18), WT late-trained (n = 18), WT early-trained (n = 19), Rett naive (n = 19), Rett late-trained (n = 19) and Rett early-trained (n = 18) mice. g, Timeline for additional behavioural assays in mice trained in the Morris water maze. h–o, After testing in the Morris water maze at 12 weeks of age, WT naive (n = 11), Rett naive (n = 12), WT late-trained (n = 11), Rett late-trained (n = 12), WT early-trained (n = 12) and Rett early-trained (n = 11) mice were tested on a variety of behavioural assays. h–j, Motor function was tested in rotarod (h), footslip (i) and open-field assays (j). k, Body weight was measured. l, Social behaviour was tested in the three-chamber assay. m, Anxiety was tested in the elevated plus maze. n, o, Sensorimotor gating was tested in the acoustic startle (n) and prepulse inhibition (o) assays. The sample size (n) corresponds to the number of biologically independent mice. Data are represented as means ± s.e.m. Statistical significance was determined using a two-tailed, unpaired Student’s t-test (b, c) or two-way ANOVA with Tukey’s multiple comparisons test (a, d–o); ns, P > 0.05; ****P < 0.0001.
Extended Data Fig. 3 FosTRAP labels task-specific neurons, including MeCP2+ and MeCP2− neurons in Rett mice.
a, Schematic showing FosTRAP. In the presence of 4-HT, neural activity activates cFos expression and subsequent expression of a Cre-dependent reporter, tdTomato. b, FosTRAP labels a subset of neurons following 4-HT administration. c–f, FosTRAP labelling during the Morris water maze experiment labels neurons in multiple brain regions. c, d, Labelled neurons in the cortex (c) and hippocampus (d) of 13-week-old mice that were trained in the Morris water maze and injected with vehicle or 4-HT, as well as mice that were handled and injected with 4-HT. tdT, tdTomato. e, f, Quantification in the cortex (e) and hippocampus (f) of WT (n = 3) and Rett (n = 4) mice. MWM, Morris water maze. Scale bars, 200 μm. g–l, FosTRAP labelling in MeCP2+ and MeCP2− neurons. g, j, FosTRAP labels NeuN+/MeCP2+ neurons in the cortex (g) and hippocampus (j) of WT mice. h, k, FosTRAP labels NeuN+/MeCP2+ and NeuN+/MeCP2− neurons in the cortex (h) and hippocampus (k) of Rett mice. i, l, Quantification of labelled neurons in the cortex (i) and hippocampus (l) of WT (n = 3) and Rett (n = 4) mice. Asterisks denote MeCP2+ neurons; hash tags denote MeCP2− neurons. Scale bars, 20 μm. The sample size (n) corresponds to the number of biologically independent mice. Three to four sections were analysed per mouse. Data are represented as means ± s.e.m. Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05; ****P < 0.0001.
Extended Data Fig. 4 Neurons associated with learning in the Morris water maze are reactivated during the Morris water maze but not during fear conditioning.
a, FosTRAP labelling of neurons associated with the Morris water maze, with subsequent reactivation of task-specific neurons during retesting in the Morris water maze or fear conditioning assay. b–d, Reactivation of cFos in neurons associated with the Morris water maze in early-trained mice retested in the Morris water maze (b), early-trained mice tested in a new fear conditioning (FC) assay (c), and late-trained mice retested in the Morris water maze (d) at 13 weeks of age. e, f, The numbers of tdTomato+, cFos+ and tdT+cFos+ neurons were quantified in the cortex (e) and hippocampus (f) of early-trained WT (n = 3) and Rett (n = 4) mice and late-trained WT (n = 3) and Rett (n = 3) mice after retesting in the Morris water maze. g, h, The numbers of tdTomato+, cFos+ and tdT+cFos+ neurons were quantified in the cortex (g) and hippocampus (h) of early-trained WT (n = 4) and Rett (n = 3) mice after fear conditioning. i, j, Reactivation percentages, defined as the percentages of tdT+ neurons that were also cFos+, were quantified in the cortex (i) and hippocampus (j) of mice trained in the Morris water maze after retesting in the maze or the fear conditioning assay. Scale bars, 200 μm. The sample size (n) corresponds to the number of biologically independent mice. Three to four sections were analysed per mouse. Data are represented as means ± s.e.m. Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05; **P < 0.01; ****P < 0.0001.
Extended Data Fig. 5 Viral delivery of DREADD-containing AAVs labels task-specific neurons, including MeCP2+ and MeCP2− neurons in Rett mice.
a, AAV-mediated delivery at P0 of Cre-dependent mCherry into cFosCreER mice that also contain a Cre-dependent GFP in the Rosa26 locus. Expression of mCherry in GFP+ neurons demonstrates that the AAVs are reactivated in task-specific neurons. b, Overlap between injected AAV (mCherry) and endogenous reporter (GFP) expression in early-trained mice at 13 weeks of age. c, Quantification of GFP+ cells, mCherry+ cells and their overlap in the cortex and hippocampus of WT (n = 3) and Rett (n = 4) mice. Scale bar, 200 μm. d–i, FosTRAP labelling in MeCP2+ and MeCP2− neurons from AAV-injected mice trained in the Morris water maze. d, g, FosTRAP labels MeCP2+ neurons in the cortex (d) and hippocampus (g) of WT mice. e, h, FosTRAP labels MeCP2+ and MeCP2− neurons in the cortex (e) and hippocampus (h) of Rett mice. f, i, Quantification in the cortex (f) and hippocampus (i) of WT (n = 3) and Rett (n = 4) mice. Asterisks denote MeCP2+ neurons; hash tags denote MeCP2− neurons. Scale bars, 20 μm. The sample size (n) corresponds to the number of biologically independent mice. Three to four sections were analysed per mouse. Data are represented as means ± s.e.m. Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05.
Extended Data Fig. 6 CNO prevents reactivation of hM4Di-expressing neurons.
a–d, Reactivation of cFos in task-specific neurons expressing mCherry or hM4Di–mCherry. a, c, Overlap between cFos and mCherry in the cortex (a) and hippocampus (c) of mice injected with CNO during testing in the Morris water maze at 13 weeks of age. b, d, Quantification of mCherry+ cells and reactivation in the cortex (b) and hippocampus (d) in WT (n = 4) and Rett (n = 4) mice. Scale bar, 200 μm. e, The effect of removing CNO on performance in the Morris water maze in 13-week-old WT mCherry (n = 6), Rett mCherry (n = 5), WT hM4Di (n = 5) and Rett hM4Di (n = 6) mice. The sample size (n) corresponds to the number of biologically independent mice. Three to four sections were analysed per mouse. Data are represented as means ± s.e.m. Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05; *P < 0.05; ****P < 0.0001.
Extended Data Fig. 7 CNO reactivates hM3Dq-expressing neurons.
a–d, Reactivation of cFos in task-specific neurons expressing mCherry or hM3Dq–mCherry. a, c, Overlap between expression of cFos and mCherry in the cortex (a) and hippocampus (c) of mice injected with CNO in the home cage at 13 weeks of age. b, d, Quantification of mCherry+ cells and reactivation in cortex (b) and hippocampus (d) of WT (n = 4) and Rett (n = 4) mice. Scale bars, 200 μm. The sample size (n) corresponds to the number of biologically independent mice. Three to four sections were analysed per mouse. Data are represented as means ± s.e.m. Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05; ****P < 0.0001.
Extended Data Fig. 8 Repeated activation of a random subset of neurons does not alter the performance of early-trained mice.
a, Paradigm for the injection of AAVs to express DREADDs in a random subset of neurons and to manipulate their activity with CNO. High-titre AAVs are delivered to cFosCreER mice, which express Cre in task-specific neurons following the administration of 4-HT. Low-titre AAVs are delivered to Camk2aCreER mice, which express Cre ubiquitously in excitatory neurons following administration of 4-HT. cFosCreER and Camk2aCreER mice express the same number of labelled neurons, but those in cFosCreER mice are task-specific. Viral titre is defined as genome copies (gc) per microlitre. b–d, Overlap between the expression of mCherry (via injected AAV) and endogenous reporter (GFP) in early-trained mice at 13 weeks of age (b); and quantification of mCherry+ cells in the cortex (c) and hippocampus (d) of WT (n = 3) and Rett (n = 4) mice expressing cFosCreER and WT (n = 4) and Rett (n = 4) expressing Camk2aCreER. Scale bars, 200 μm. e, f, Reactivation of cFos in Camk2aCreER mice expressing mCherry (e); and quantification of reactivation in the cortex and hippocampus of 13-week-old WT (n = 4) and Rett (n = 3) mice after training in the Morris water maze (f). g–i, Performance in the Morris water maze of early-trained WT and Rett mice expressing Camk2aCreER and hM4Di–mCherry or mCherry. g, WT mCherry (n = 7), Rett mCherry (n = 8), WT hM4Di (n = 8) and Rett hM4Di (n = 6) mice were tested at 13 weeks of age and injected with CNO during testing. h, i, A probe trial on day 6 measured the time spent in the target quadrant (h) and the number of crossings of the platform area (i). j, k, Performance in the Morris water maze of early-trained WT and Rett mice expressing Camk2aCreER and hM3Dq–mCherry or mCherry. A probe trial of WT mCherry (n = 7), Rett mCherry (n = 8), WT hM3Dq (n = 7) and Rett hM3Dq (n = 7) mice measured the time spent in the target quadrant (j) and the number of crossings of the platform area (k). The sample size (n) corresponds to the number of biologically independent mice. Data are represented as means ± s.e.m. Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05.
Extended Data Fig. 9 Morphological and electrophysiological benefits are evident in task-specific neurons after presymptomatic training.
a, AAV-mediated delivery of yellow fluorescent protein (YFP) at P0 to assess the morphology of neurons that are not task-specific (tdT−). b–e, Morphological analysis of MeCP2− hippocampal CA1 neurons that are task-specific (tdT+) and not task-specific (tdT−/YFP+) in trained Rett mice at 13 weeks of age. Sholl analysis (b) and measurement of spine density (c), soma area (d) and nuclear area (e) in MeCP2− neurons of late-trained (n = 5) and early-trained (n = 5) Rett mice. f–j, Electrophysiological recordings of MeCP2− CA1 neurons in late- and early-trained Rett mice at 13 weeks of age. f, Representative images of neurons that are task-specific (magenta) and not task-specific (no magenta), both of which were injected with biocytin (green) during recording and immunostained to determine the MeCP2 status (yellow). g–j, Frequency (g) and amplitude (h) of sIPSCs and frequency (i) and amplitude (j) of sEPSCs were measured in MeCP2− neurons from late-trained (n = 10) and early-trained (n = 10) Rett mice. The sample size (n) corresponds to the number of biologically independent mice. For b, c, 10–15 neurons were analysed per mouse. For d, e, 50–100 neurons were analysed per mouse. For g–j, one to three neurons were analysed per mouse. Data are represented as means ± s.e.m. Statistical significance was determined using one-way (b) or two-way (c–e, g–j) ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05; **P < 0.01; ****P < 0.0001.
Extended Data Fig. 10 Presymptomatic training improves the dendritic morphology of task-specific hippocampal granule and cortical neurons in Rett mice.
a–d, Morphological analysis of task-specific hippocampal granule neurons in late- and early-trained WT and Rett mice at 13 weeks of age. Sholl analysis (a) and measurement of spine density (b), soma area (c) and nuclear area (d) in neurons of WT late-trained (n = 5), WT early-trained (n = 5), Rett late-trained MeCP2− (n = 5), Rett early-trained MeCP2+ (n = 5) and Rett early-trained MeCP2− (n = 5) neurons. e–h, Morphological analysis of layer-5 cortical task-specific neurons in late- and early-trained WT and Rett mice. Sholl analysis (e) and measurement of spine density (f), soma area (g) and nuclear area (h) in neurons of WT late-trained (n = 5), WT early-trained (n = 5), Rett late-trained MeCP2+ (n = 5), Rett late-trained MeCP2− (n = 5), Rett early-trained MeCP2+ (n = 5), and Rett early-trained MeCP2− (n = 5) neurons. The sample size (n) corresponds to the number of biologically independent mice. For a, b, e–g, 10–15 neurons were analysed per mouse. For c, d, g, h, 50–100 neurons were analysed per mouse. Data are represented as means ± s.e.m. Statistical significance was determined using one-way (b–d, f–h) and two-way (a, e) ANOVA with Tukey’s multiple comparisons test; ns, P > 0.05; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
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Achilly, N.P., Wang, W. & Zoghbi, H.Y. Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome. Nature 592, 596–600 (2021). https://doi.org/10.1038/s41586-021-03369-7
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DOI: https://doi.org/10.1038/s41586-021-03369-7
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