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.
Highlights
Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder, mainly caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), a protein involved in transcriptional regulation (Amir et al, 1999; Wan et al, 1999; Xiang et al, 2000)
paired-pulse ratio (PPR) and Pvr remained unchanged in all conditions (Figure 2J–L). These results strongly suggest that Brain-Derived Neurotrophic Factor (BDNF) synthesis and an active BDNF-TrkB pathway are essential for normal neuronal growth in WT as well as RTT-like hippocampal glutamatergic neurons. Consistent with these results, we show that treatment of BDNF overexpressing Mecp2Null/ y neurons with an anti-BDNF neutralizing antibody (Figure 3A) decreased Excitatory postsynaptic currents (EPSCs) amplitude and readily releasable pool (RRP) size by 50 and 53% respectively (Figure 3B–E), thereby negating phenotype rescue seen via BDNF overexpression
We find a critical role for BDNF
Summary
Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder, mainly caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), a protein involved in transcriptional regulation (Amir et al, 1999; Wan et al, 1999; Xiang et al, 2000). RTT patients show regression of head growth followed by various neurological symptoms including seizures, mental retardation, stereotypic hand-wringing movements, breathing irregularities, ataxia and autistic behavior (Rett, 1966). Mouse models with Mecp mutations display similar neurological phenotypes, and have been quite critical in defining the pathophysiology of RTT. Mecp2Null/y mice grow normally until 4–6 weeks of age, after which they display RTT-like symptoms such as reduced mobility, hindlimb clasping, abnormal breathing patterns and premature death (Chen et al, 2001; Guy et al, 2001).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
