BDNF-Dependent Recycling Facilitates TrkB Translocation to Postsynaptic Density during LTP via a Rab11-Dependent Pathway

Abstract

Brain-derived neurotrophic factor (BDNF) plays an important role in the activity-dependent regulation of synaptic structure and function via tropomyosin related kinase B (TrkB) receptor activation. However, whether BDNF could regulate TrkB levels at synapse during long-term potentiation (LTP) is still unknown. We show in cultured rat hippocampal neurons that chemical LTP (cLTP) stimuli selectively promote endocytic recycling of BDNF-dependent full-length TrkB (TrkB-FL) receptors, but not isoform T1 (TrkB.T1) receptors, via a Rab11-dependent pathway. Moreover, neuronal-activity-enhanced TrkB-FL recycling could facilitate receptor translocation to postsynaptic density and enhance BDNF-induced extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation and rat hippocampal neuron survival. Finally, we found that cLTP could stimulate the switch of Rab11 from an inactive to an active form and that GTP-bound Rab11 could enhance the interaction between TrkB-FL and PSD-95. Therefore, the recycling endosome could serve as a reserve pool to supply TrkB-FL receptors for LTP maintenance. These findings provide a mechanistic link between Rab11-dependent endocytic recycling and TrkB modulation of synaptic plasticity.

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

“…However, BDNF and its propeptide have been found in presynaptic dense core vesicles, but not in the postsynaptic dendrites of the adult mouse hippocampus (6), suggesting an anterograde mode of action of BDNF. Previous work has shown that extracellular BDNF released by either pre-or postsynaptic neurons could be recycled back to the synaptic sites via binding to TrkB receptors on the dendrites of postsynaptic neurons (46,47). In the present work, we further showed that BDNF could be internalized and released at postsynaptic sites via physiologically Fig.…”

Myosin5a mediates BDNF-induced postendocytic recycling of full-length TrkB and its translocation into dendritic spines

“…In our previous studies, we found that Rab11 associates with TrkB-FL and mediates its postendocytic recycling (Huang et al, 2013). It has also been reported that Rab11 associates with Myo5a and mediates the trafficking cargos such as AMPA receptors (Correia et al, 2008;Roland et al, 2009;Lindsay et al, 2013).…”

“…Next, we investigated whether Myo5a participated in the postendocytic recycling of TrkB-FL. We used a live-cell ratiometric fluorescence-based recycling assay, which has been widely used in our previous studies (Chen et al, 2005;Huang et al, 2009;Huang et al, 2013), to measure the recycling levels of TrkB-FL (Fig. 4A).…”

“…It has been established that the TrkB receptors can be sorted to the recycling pathway after BDNF-triggered endocytosis (Grimes et al, 1997;Chen et al, 2005). Our previous work has shown that full-length TrkB (TrkB-FL) and the T1 isoform (TrkB.T1) are sorted into different recycling pathways after endocytosis: TrkB.T1 can rapidly recycle back to the neuronal surface through a Rab4-mediated 'fast recycling' pathway, whereas TrkB-FL goes into a Rab11-mediated 'slow recycling' pathway Huang et al, 2013). Myosin VI has been found to mediate the internalization of TrkB receptors (Yano et al, 2006), but the motor proteins that mediate the postendocytic recycling of TrkB receptors have not yet been identified.…”

Crystal Structure of the cGMP-dependent Protein Kinase II Leucine Zipper and Rab11b Protein Complex Reveals Molecular Details of G-kinase-specific Interactions

“…Specifically, it was shown that PKG II interacts with GDP-bound Rab11b and that this interaction is crucial for their co-localization at the recycling endosome and their subsequent return to the plasma membrane (26). Rab11 has also been reported to interact with other membrane-associated proteins such as the ␤ 2 -adrenergic receptor, TRPV5 and TRPV6 Ca 2ϩ channels, b-isoform of the thromboxane A 2 receptor (TPb), and brain-derived neurotrophic factordependent TrkB (TrkB-FL) receptors (27)(28)(29)(30).…”