Activity-Dependent Release of Endogenous BDNF From Mossy Fibers Evokes a TRPC3 Current and Ca2+ Elevations in CA3 Pyramidal Neurons
Activity-Dependent Release of Endogenous BDNF From Mossy Fibers Evokes a TRPC3 Current and Ca2+ Elevations in CA3 Pyramidal Neurons
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DOI：
10.1152/jn.01140.2009
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发表时间：
2010-05-01
影响因子：
2.5
通讯作者：
Pozzo-Miller, Lucas
中科院分区：
文献类型：
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作者：
Li, Yong;Calfa, Gaston;Pozzo-Miller, Lucas
LI Y，Calfa G，Inoue T，Amaral MD，Pozzo-Miller L.苔藓纤维内源性BDNF的活性依赖性释放在CA3锥体神经元上引起TRPC3电流和钙离子升高。神经生理学杂志103：2846-2856,2010。2010年3月10日首次出版；DOI：10.1152/jn.01140.2009。多项研究表明，脑源性神经营养因子(BDNF)是海马区神经元结构和功能的有效调节剂。然而，到目前为止，大多数研究都依赖于重组BDNF的应用。我们在此报道，通过刺激苔藓纤维(Mf)而释放的内源性BDNF，在CA3锥体神经元上引起缓慢发展的阳离子电流和细胞内Ca~(2+)升高，其药理特征与短暂定位应用重组BDNF在CA1神经元上激活的瞬时受体电位规范3(TRPC3)介导的i-BDNF相同。事实上，对细胞外BDNF清除剂原肌球蛋白相关激酶B(TrkB)-Ig G和小发夹干扰RNA介导的TRPC3通道阻断的敏感性证实了这种电导的同一性，此后将其命名为MF-I-BDNF。与这种活性依赖的BDNF释放一致，这些MF-I-BDNF反应对胞外锌离子浓度的操纵不敏感。短时刺激MFS引起AMPA和N-甲基-D-天冬氨酸(NMDA)受体介导的兴奋性突触后电流(EPSCs)幅度的持久抑制，但不改变NMDA受体/AMPA受体的比率，提示神经递质释放减少。NMDAR介导的EPSCs的这种抑制需要内源性BDNF从MFS中活性依赖地释放和Trk受体的激活，因为它对细胞外BDNF清除剂TrkB-Ig G和酪氨酸激酶抑制剂k-252b敏感。这些结果揭示了海马神经元对内源性释放的天然脑源性神经营养因子的最直接反应，并进一步证实了脑源性神经营养因子信号与海马区突触功能的相关性。
Li Y, Calfa G, Inoue T, Amaral MD, Pozzo-Miller L. Activity-dependent release of endogenous BDNF from mossy fibers evokes a TRPC3 current and Ca2+ elevations in CA3 pyramidal neurons. J Neurophysiol 103: 2846-2856, 2010. First published March 10, 2010; doi: 10.1152/jn.01140.2009. Multiple studies have demonstrated that brain-derived neurotrophic factor (BDNF) is a potent modulator of neuronal structure and function in the hippocampus. However, the majority of studies to date have relied on the application of recombinant BDNF. We herein report that endogenous BDNF, released via theta burst stimulation of mossy fibers (MF), elicits a slowly developing cationic current and intracellular Ca2+ elevations in CA3 pyramidal neurons with the same pharmacological profile of the transient receptor potential canonical 3 (TRPC3)-mediated I-BDNF activated in CA1 neurons by brief localized applications of recombinant BDNF. Indeed, sensitivity to both the extracellular BDNF scavenger tropomyosin-related kinase B (TrkB)-IgG and small hairpin interference RNA-mediated TRPC3 channel knockdown confirms the identity of this conductance as such, henceforth-denoted MF-I-BDNF. Consistent with such activity-dependent release of BDNF, these MF-I-BDNF responses were insensitive to manipulations of extracellular Zn2+ concentration. Brief theta burst stimulation of MFs induced a long-lasting depression in the amplitude of excitatory postsynaptic currents (EPSCs) mediated by both AMPA and N-methyl-D-aspartate (NMDA) receptors without changes in the NMDA receptor/AMPA receptor ratio, suggesting a reduction in neurotransmitter release. This depression of NMDAR-mediated EPSCs required activity-dependent release of endogenous BDNF from MFs and activation of Trk receptors, as it was sensitive to the extracellular BDNF scavenger TrkB-IgG and the tyrosine kinase inhibitor k-252b. These results uncovered the most immediate response to endogenously released-native -BDNF in hippocampal neurons and lend further credence to the relevance of BDNF signaling for synaptic function in the hippocampus.