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

LI W, CALFA G, LARIMORE J, POZZO-MILLER L

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2012 p. 1 - 6

0027-8424

Dysfunction of the neurotrophin brain-derived neurotrophic factor(BDNF) is implicated in Rett syndrome (RTT), but the state of itsreleasable pool and downstream signaling in mice lacking methyl-CpG-binding protein-2 (Mecp2) is unknown. Here, we show thatmembrane currents and dendritic Ca2+ signals evoked by recombinantBDNF or an activator of diacylglycerol (DAG)-sensitive transientreceptor potential canonical (TRPC) channels are impaired inCA3 pyramidal neurons of symptomatic Mecp2 mutant mice.TRPC3 and TRPC6 mRNA and protein levels are lower in Mecp2mutant hippocampus, and chromatin immunoprecipitation (ChIP)identified Trpc3 as a target of MeCP2 transcriptional regulation.BDNF mRNA and protein levels are also lower in Mecp2 mutanthippocampus and dentate gyrus granule cells, which is reflected inimpaired activity-dependent release of endogenous BDNF estimatedfrom TRPC currents and dendritic Ca2+ signals in CA3 pyramidalneurons. These results identify the gene encoding TRPC3channels as a MeCP2 target and suggest a potential therapeuticstrategy to boost impaired BDNF signaling in RTT.