Autocrine BDNF-TrkB signalling within a single dendritic spine.
Autocrine BDNF-TrkB signalling within a single dendritic spine.
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DOI：
10.1038/nature19766
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发表时间：
2016-10-06
期刊：
影响因子：
64.8
通讯作者：
McNamara JO
中科院分区：
文献类型：
--
作者：
Harward SC;Hedrick NG;Hall CE;Parra-Bueno P;Milner TA;Pan E;Laviv T;Hempstead BL;Yasuda R;McNamara JO
脑源性神经营养因子（BDNF）及其受体TrkB对许多形式的神经元可塑性至关重要，包括与动物学习相关的结构长时程增强（sLTP）。然而，尚不清楚BDNF释放和TrkB激活是否发生在sLTP期间，以及如果发生，何时何地。在这里，使用荧光共振能量转移为基础的传感器的TrkB和双光子荧光寿命成像显微镜，我们监测TrkB活性在单个树突棘的CA 1锥体神经元在培养的小鼠海马切片。响应于sLTP诱导，我们发现受刺激的脊柱中TrkB的快速（发作< 1分钟）和持续（>20分钟）激活，其依赖于NMDAR（N-甲基-d-天冬氨酸受体）和CaMKII信号传导以及突触后合成的BDNF。我们确认突触后BDNF的存在，使用电子显微镜本地化内源性BDNF的树突和海马CA 1区锥体神经元的棘。与这些研究结果一致，我们还显示了快速，谷氨酸释放诱发的，时间锁定的BDNF释放从单个树突棘使用BDNF融合superecliptic pHluorin。我们证明，这种突触后BDNF-TrkB信号通路是必要的结构和功能的LTP。总之，这些研究结果揭示了一个脊柱自主，自分泌信号传导机制，涉及NMDAR-CaMKII依赖性BDNF从刺激的树突棘释放和随后的TrkB激活这些相同的棘，这是至关重要的结构和功能可塑性。
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for many forms of neuronal plasticity, including structural long-term potentiation (sLTP), which is a correlate of an animal’s learning. However, it is unknown whether BDNF release and TrkB activation occur during sLTP, and if so, when and where. Here, using a fluorescence resonance energy transfer-based sensor for TrkB and two-photon fluorescence lifetime imaging microscopy, , we monitor TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured murine hippocampal slices. In response to sLTP induction, we find fast (onset < 1 min) and sustained (>20 min) activation of TrkB in the stimulated spine that depends on NMDAR (N-methyl-d-aspartate receptor) and CaMKII signalling and on postsynaptically synthesized BDNF. We confirm the presence of postsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines of hippocampal CA1 pyramidal neurons. Consistent with these findings, we also show rapid, glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines using BDNF fused to superecliptic pHluorin. We demonstrate that this postsynaptic BDNF–TrkB signalling pathway is necessary for both structural and functional LTP. Together, these findings reveal a spine-autonomous, autocrine signalling mechanism involving NMDAR–CaMKII-dependent BDNF release from stimulated dendritic spines and subsequent TrkB activation on these same spines that is crucial for structural and functional plasticity.