Activity-dependent BDNF release and TRPC signaling is impaired in hippocampal neurons of Mecp2 mutant mice.

Abstract

Dysfunction of the neurotrophin brain-derived neurotrophic factor (BDNF) is implicated in Rett syndrome (RTT), but the state of its releasable pool and downstream signaling in mice lacking methyl-CpG-binding protein-2 (Mecp2) is unknown. Here, we show that membrane currents and dendritic Ca(2+) signals evoked by recombinant BDNF or an activator of diacylglycerol (DAG)-sensitive transient receptor potential canonical (TRPC) channels are impaired in CA3 pyramidal neurons of symptomatic Mecp2 mutant mice. TRPC3 and TRPC6 mRNA and protein levels are lower in Mecp2 mutant hippocampus, and chromatin immunoprecipitation (ChIP) identified Trpc3 as a target of MeCP2 transcriptional regulation. BDNF mRNA and protein levels are also lower in Mecp2 mutant hippocampus and dentate gyrus granule cells, which is reflected in impaired activity-dependent release of endogenous BDNF estimated from TRPC currents and dendritic Ca(2+) signals in CA3 pyramidal neurons. These results identify the gene encoding TRPC3 channels as a MeCP2 target and suggest a potential therapeutic strategy to boost impaired BDNF signaling in RTT.

• Authors: Wei Li, Gaston Calfa, Jennifer Larimore, Lucas Pozzo-Miller
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 42 Pg. 17087-92 (Oct 16 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 23027959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• Mecp2 protein, mouse
• Methyl-CpG-Binding Protein 2
• TRPC Cation Channels

Topics

• Animals
• Blotting, Western
• Brain-Derived Neurotrophic Factor (metabolism)
• Hippocampus (cytology)
• Immunohistochemistry
• Methyl-CpG-Binding Protein 2 (genetics)
• Mice
• Mice, Mutant Strains
• Microscopy, Confocal
• Patch-Clamp Techniques
• Pyramidal Cells (physiology)
• Real-Time Polymerase Chain Reaction
• Rett Syndrome (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• TRPC Cation Channels (metabolism)