title: Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons.
abstract: Mutations in theMECP2gene 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 neuronsin vitroandin vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system.
authors: Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: Charanya
authors: C
authors: Sampathkumar
authors: Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: Yuan-Ju
authors: YJ
authors: Wu
authors: NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.|Institute of Biochemistry, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: Mayur
authors: M
authors: Vadhvani
authors: Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: Thorsten
authors: T
authors: Trimbuch
authors: NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.|Institute of Biochemistry, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: Britta
authors: B
authors: Eickholt
authors: Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: Christian
authors: 0000-0002-3905-2444
authors: C
authors: Rosenmund
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D015518:Rett Syndrome / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2
keywords: BDNF; Rett syndrome; cell autonomous; glutamatergic; mouse; neuroscience; synaptic transmission