Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 27, Pages 11246-11251Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1012401108
Keywords
gene expression; mRNA translation
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Funding
- Life Sciences Research Foundation
- National Institute on Drug Abuse [T32DA007274]
- German Research Foundation fellowship Deutsche Forschungsgemeinschaft Forschungsstipendium
- March of Dimes [12-FY07-261]
- National Institutes of Health [DA023581, NS056306]
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Signaling from dendritic synapses to the nucleus regulates important aspects of neuronal function, including synaptic plasticity. The neurotrophin brain-derived neurotrophic factor (BDNF) can induce long-lasting strengthening of synapses in vivo and this effect is dependent on transcription. However, the mechanism of signaling to the nucleus is not well understood. Here we describe a microfluidic culture device to investigate dendrite-to-nucleus signaling. Using these microfluidic devices, we demonstrate that BDNF can act directly on dendrites to elicit an anterograde signal that induces transcription of the immediate early genes, Arc and c-Fos. Induction of Arc is dependent on dendrite- and cell body-derived calcium, whereas induction of c-Fos is calcium-independent. In contrast to retrograde neurotrophin-mediated axon-to-nucleus signaling, which is MEK5-dependent, BDNF-mediated anterograde dendrite-to-nucleus signaling is dependent on MEK1/2. Intriguingly, the activity of TrkB, the BDNF receptor, is required in the cell body for the induction of Arc and c-Fos mediated by dendritically applied BDNF. These results are consistent with the involvement of a signaling endosome-like pathway that conveys BDNF signals from the dendrite to the nucleus.
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