Endocytic BDNF secretion regulated by Vamp3 in astrocytes

Abstract

Brain-derived neurotrophic factor (BDNF) regulates diverse brain functions via TrkB receptor signaling. Due to the expression of TrkB receptors, astrocytes can internalize extracellular BDNF proteins via receptor-mediated endocytosis. Endocytosed BDNF can be re-secreted upon stimulation, but the molecular mechanism underlying this phenomenon remains unrecognized. Our study reveals that vesicle-associated membrane protein 3 (Vamp3) selectively regulates the release of endocytic BDNF from astrocytes. By using quantum dot (QD)-conjugated mature BDNF (QD-BDNF) as a proxy for the extracellular BDNF protein, we monitored the uptake, transport, and secretion of BDNF from cultured cortical astrocytes. Our data showed that endocytic QD-BDNF particles were enriched in Vamp3-containing vesicles in astrocytes and that ATP treatment sufficiently triggered either the antero- or retrograde transport and exocytosis of QD-BDNF-containing vesicles. Downregulation of Vamp3 expression disrupted endocytic BDNF secretion from astrocytes but did not affect uptake or transport. Collectively, these results provide evidence of the selective ability of astrocytic Vamp3 to control endocytic BDNF secretion during BDNF recycling.

Molecular mechanisms underlying physical exercise-induced brain BDNF overproduction

“…The nearby astrocytes end-feet able to internalize it through TrkB-T1 receptor could then transfer BDNF to neighboring neurons via transcytosis or a related mechanism. Recent research by Han et al (2021) showing in astrocyte recycling, the re-secretion of TrkB-endocytic BDNF substantiates this theory. Consequently, the released BDNF from astrocytes into the extracellular space could bind to neuronal TrkB-FL triggering neuroplastic signaling pathway.…”

Perirhinal Cortex LTP Does Not Require Astrocyte BDNF-TrkB Signaling

“…In contrast to proBDNF recycling, other studies suggest that solely the mature BDNF is endocytosed by astrocytes via full-length TrkB [27] or truncated t-TrkB receptors [28]. In the first case, the catalytically active TrkB orchestrates BDNF recycling, through which BDNF is initially internalized and then re-released [27].…”

Mechanisms Controlling the Expression and Secretion of BDNF

“…In addition, complexin1, which activates and clamps vesicular exocytosis interacting with SNARE proteins, is required for activity-dependent exocytosis of BDNF at postsynaptic sites, but at the same time it prevents spontaneous exocytosis of docked endosomes [159]. Additionally, the protein Vamp3 has been recently implicated in BDNF release from endocytosed BDNF [160]. Thus, using different proteins, endocytosed BDNF can be stored with the activity-dependent releasable pool required for LTP maintenance.…”