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Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome

Smith ES 1 , Smith DR 2 , Eyring C 3 , Braileanu M 4 , Smith-Connor KS 3 , Ei Tan Y 5 Show all authors , Fowler AY 6 , Hoffman GE 6 , Johnston MV 7 , Kannan S 8 , Blue ME 9

Affiliations 

  • 1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • 2 Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218, USA
  • 3 The Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, USA
  • 4 Undergraduate Program in Neuroscience, The Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA
  • 5 Perdana University Graduate School of Medicine, Kuala Lumpur, Malaysia
  • 6 Department of Biology, Morgan State University, Baltimore, MD 21251, USA
  • 7 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, USA
  • 8 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, USA
  • 9 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, USA. Electronic address: blue@kennedykrieger.org
Neurobiol Learn Mem, 2019 Nov;165:106962.
PMID: 30502397 DOI: 10.1016/j.nlm.2018.11.007

Abstract

Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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