Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons
- Charité Universitätsmedizin Berlin, Germany
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
Christian Rosenmund
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.
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).
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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Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons
eLife 5:e19374.
https://doi.org/10.7554/eLife.19374
