Elevated MeCP2 in Mice Causes Neurodegeneration Involving Tau Dysregulation and Excitotoxicity: Implications for the Understanding and Treatment of MeCP2 Triplication Syndrome

  • Kristen R. Montgomery
  • A. S. C. Louis Sam Titus
  • Lulu Wang
  • Santosh R. D’Mello


Expression of MeCP2 must be carefully regulated as a reduction or increase results in serious neurological disorders. We are studying transgenic mice in which the MeCP2 gene is expressed at about three times higher than the normal level. Male MeCP2-Tg mice, but not female mice, suffer motor and cognitive deficits and die at 18–20 weeks of age. MeCP2-Tg mice display elevated GFAP and Tau expression within the hippocampus and cortex followed by neuronal loss in these brain regions. Loss of Purkinje neurons, but not of granule neurons in the cerebellar cortex is also seen. Exposure of cultured cortical neurons to either conditioned medium from astrocytes (ACM) derived from male MeCP2-Tg mice or normal astrocytes in which MeCP2 is expressed at elevated levels promotes their death. Interestingly, ACM from male, but not female MeCP2-Tg mice, displays this neurotoxicity reflecting the gender selectivity of neurological symptoms in mice. Male ACM, but not female ACM, contains highly elevated levels of glutamate, and its neurotoxicity can be prevented by MK-801, indicating that it is caused by excitotoxicity. Based on the close phenotypic resemblance of MeCP2-Tg mice to patients with MECP2 triplication syndrome, we suggest for the first time that the human syndrome is a neurodegenerative disorder resulting from astrocyte dysfunction that leads to Tau-mediated excitotoxic neurodegeneration. Loss of cortical and hippocampal neurons may explain the mental retardation and epilepsy in patients, whereas ataxia likely results from the loss of Purkinje neurons.


MeCP2 triplication syndrome Tau GFAP Astrocyte dysfunction Neurodegeneration 



This research was supported by a grant from the National Institutes of Health (R01 NS040408). We thank Dr. Jade Franklin for making significant contributions to the research and the preparation of figures for the manuscript. We also acknowledge the contribution of Dr. Xiaoju Zou for her assistance with some of the immunohistology work described in the manuscript.

Supplementary material

12035_2018_1046_Fig14_ESM.gif (28 kb)
Supplemental Figure 1

(A and B) Locomotor analysis at 15 weeks of age in WT and MeCP2-Tg female mice (n = 6). (C and D) Forelimb and hindlimb grip strength at 15 weeks of age in WT and MeCP2-Tg female mice (n = 6). (E) Brain Weight of 15-week-old WT and MeCP2-Tg female Mice (n = 6). (F) Body Weight of 15-week-old WT and MeCP2-Tg female mice (n = 6). (GIF 28 kb).

12035_2018_1046_MOESM1_ESM.tif (191 kb)
High Resolution Image (TIFF 191 kb).
12035_2018_1046_Fig15_ESM.gif (15 kb)
Supplemental Figure 2

Male WT and MeCP2-Tg mice (blue), display elevated Tau that correlates to increases in MeCP2 expression (n = 11). Female WT and MeCP2-Tg mice (red) do not display the same correlation (n = 8). (GIF 14 kb).

12035_2018_1046_MOESM2_ESM.tif (165 kb)
High Resolution Image (TIFF 165 kb).


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kristen R. Montgomery
    • 1
  • A. S. C. Louis Sam Titus
    • 1
  • Lulu Wang
    • 1
  • Santosh R. D’Mello
    • 1
  1. 1.Department of Biological SciencesSouthern Methodist UniversityDallasUSA

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