Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

Abstract

Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system.

Article and author information

Author details

  1. Charanya Sampathkumar

    Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    No competing interests declared.
  2. Yuan-Ju Wu

    Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    No competing interests declared.
  3. Mayur Vadhvani

    Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    No competing interests declared.
  4. Thorsten Trimbuch

    Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    No competing interests declared.
  5. Britta Eickholt

    NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    No competing interests declared.
  6. Christian Rosenmund

    Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany
    For correspondence
    christian.rosenmund@charite.de
    Competing interests
    Christian Rosenmund, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3905-2444

Funding

Deutsche Forschungsgemeinschaft (SFB 665)

  • Charanya Sampathkumar
  • Mayur Vadhvani
  • Christian Rosenmund

Deutsche Forschungsgemeinschaft (Exc257)

  • Yuan-Ju Wu
  • Mayur Vadhvani
  • Britta Eickholt
  • Christian Rosenmund

Berlin Institute of Health (CRG Congenital Diseases)

  • Charanya Sampathkumar
  • Christian Rosenmund

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Ethics

Animal experimentation: All procedures to maintain and use mice were approved by the Animal Welfare Committee of Charité Medical University and the Berlin State Government (License no. 0220/09).

Version history

  1. Received: July 4, 2016
  2. Accepted: October 25, 2016
  3. Accepted Manuscript published: October 26, 2016 (version 1)
  4. Accepted Manuscript updated: November 1, 2016 (version 2)
  5. Version of Record published: November 14, 2016 (version 3)

Copyright

© 2016, Sampathkumar et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Charanya Sampathkumar
  2. Yuan-Ju Wu
  3. Mayur Vadhvani
  4. Thorsten Trimbuch
  5. Britta Eickholt
  6. Christian Rosenmund
(2016)
Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons
eLife 5:e19374.
https://doi.org/10.7554/eLife.19374

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https://doi.org/10.7554/eLife.19374

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