Neuronal secretory pathway essential for development and maintenance of brain circuit and synaptic function

Neurons employ a diverse repertoire of trafficking organelles for secretion of solublemolecules and recycling of membrane components, and these mechanisms are essentialfor development and maintenance of brain environment. Recent studies have identified thecore components of a secretory apparatus that triggers the release of neurotransmittersfrom presynaptic terminals. Synaptic vesicle exocytosis is mediated by SNARE proteins,Synaptobrevin/VAMP2 (Syb2), SNAP25 and Syntaxin1, whose assembly into ternarycomplexes facilitate membrane fusion. A variety of diffusible peptide cues also appear tobe transported by vesicles and undergo exocytosis, supporting the hypothesis that diverseSNAREs independently control different type of membrane fusion. Among such peptidecues, the brain-derived neurotrophic factor (BDNF) is known to play many critical roles inthe nervous system. However, the molecular mechanisms that control the secretion ofBDNF and other diffusible protein cues remain largely unknown.Here, we demonstrate that, using total internal reflection fluorescence microscopy andBDNF fused to pH-sensitive GFP variant pHluorin, activity-dependent exocytosis ofBDNF from somatodendrites and axons is mediated by SNARE proteins Syb2 andSNAP25, suggesting these SNAREs act in multiple secretory pathways. Importantly,axonal secretion of BDNF is also specifically regulated by SNAP47. Cell-autonomousshRNA mediated knockdown of SNAP47 impairs the targeting and terminal branching ofcallosal axons in vivo, similar to knockdown of BDNF and its receptor TrkB. Takentogether, these novel SNARE functions in BDNF secretion provide an important insightfor neuronal circuit connectivity during brain development and/or maintenance.新学術領域 脳内環境 班会議 第2回 若手研究者シンポジウ