Bergami Matteo, Santi Spartaco, Formaggio Elena, Cagnoli Cinzia, Verderio Claudia, Blum Robert, Berninger Benedikt, Matteoli Michela, Canossa Marco
Department of Human and General Physiology, University of Bologna, I-40126 Bologna, Italy.
J Cell Biol. 2008 Oct 20;183(2):213-21. doi: 10.1083/jcb.200806137. Epub 2008 Oct 13.
Activity-dependent secretion of brain-derived neurotrophic factor (BDNF) is thought to enhance synaptic plasticity, but the mechanisms controlling extracellular availability and clearance of secreted BDNF are poorly understood. We show that BDNF is secreted in its precursor form (pro-BDNF) and is then cleared from the extracellular space through rapid uptake by nearby astrocytes after theta-burst stimulation in layer II/III of cortical slices, a paradigm resulting in long-term potentiation of synaptic transmission. Internalization of pro-BDNF occurs via the formation of a complex with the pan-neurotrophin receptor p75 and subsequent clathrin-dependent endocytosis. Fluorescence-tagged pro-BDNF and real-time total internal reflection fluorescence microscopy in cultured astrocytes is used to monitor single endocytic vesicles in response to the neurotransmitter glutamate. We find that endocytosed pro-BDNF is routed into a fast recycling pathway for subsequent soluble NSF attachment protein receptor-dependent secretion. Thus, astrocytes contain an endocytic compartment competent for pro-BDNF recycling, suggesting a specialized form of bidirectional communication between neurons and glia.
脑源性神经营养因子（BDNF）的活性依赖性分泌被认为可增强突触可塑性，但控制分泌型BDNF细胞外可用性和清除的机制却知之甚少。我们发现，BDNF以其前体形式（pro-BDNF）分泌，在皮质切片II/III层进行θ波爆发刺激（一种导致突触传递长期增强的模式）后，通过附近星形胶质细胞的快速摄取从细胞外空间清除。pro-BDNF的内化通过与泛神经营养因子受体p75形成复合物并随后通过网格蛋白依赖性内吞作用发生。在培养的星形胶质细胞中，使用荧光标记的pro-BDNF和实时全内反射荧光显微镜来监测单个内吞囊泡对神经递质谷氨酸的反应。我们发现，内吞的pro-BDNF被导向快速再循环途径，用于随后的可溶性NSF附着蛋白受体依赖性分泌。因此，星形胶质细胞含有一个能够进行pro-BDNF再循环的内吞区室，这表明神经元和神经胶质细胞之间存在一种特殊形式的双向通信。
