Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites

Abstract

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.gene expression | mRNA translation

Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin

“…Because BDNF-containing endosomes are likely to be biochemically active (12)(13)(14)(15), they could exert prolonged localized action of BDNF-TrkB signaling in the postsynaptic cytoplasm. Mobile endosomes could also spread BDNF-TrkB signals in the extrasynaptic region.…”

“…Neurotrophin binding to its receptor leads to cytoplasmic signaling as well as internalization of the neurotrophin-receptor complexes. These endocytosed neurotrophin-receptor complexes remain active in the form of "signaling endosomes" that could be transported over long distances within neuronal cytoplasm to exert its regulatory functions within the neuron (12)(13)(14)(15). In this study, we have examined the possibility that these endosomes may undergo activity-dependent exocytosis at postsynaptic dendrites, thus providing an additional source of synaptic BDNF.…”

BDNF-induced local protein synthesis and synaptic plasticity

“…A recent study using a microfluidic device that allows the isolation of the dendritic compartment showed that BDNF acts on dendrites of cultured cortical neurons to induce an signal that upregulates the expression of the IEG Arc and c-Fos (Cohen et al, 2011) (Fig. 1).…”

“…The effect of BDNF in the signaling from dendrites to the nucleus depends on MEK1/2 (MAPK and ERK kinase, type 1/ 2), and activity of the TrkB receptors to induce gene expression is required mainly in the soma compartment. However, distinct mechanisms are involved in the regulation of the expression of the two genes since the Ca 2þ concentration in the soma and in the dendritic compartments influenced the expression of Arc but not cFos (Cohen et al, 2011). Additional studies are required to identify other genes that are specifically regulated following activation of dendritic receptors for BDNF.…”

Brain-Derived Neurotrophic Factor Induces Matrix Metalloproteinase 9 Expression in Neurons via the Serum Response Factor/c-Fos Pathway

“…It is involved in rapid local changes at the synapse and has a long-term effect on the transcription of genes that are important for neuronal plasticity, such as c-Fos and Arc (2,3). BDNF plays a critical role in activitydependent synaptic plasticity, particularly long-term potentiation (LTP) (3)(4)(5)(6).…”