BDNF Activates Postsynaptic TrkB Receptors to Induce Endocannabinoid Release and Inhibit Presynaptic Calcium Influx at a Calyx-Type Synapse.
BDNF Activates Postsynaptic TrkB Receptors to Induce Endocannabinoid Release and Inhibit Presynaptic Calcium Influx at a Calyx-Type Synapse.
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BDNF 激活突触后 TrkB 受体，诱导内源性大麻素释放并抑制花萼型突触的突触前钙流入
DOI：
10.1523/jneurosci.2838-19.2020
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发表时间：
2020-10-14
期刊：
影响因子：
--
通讯作者：
Xue L
中科院分区：
文献类型：
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作者：
Wu Y;Liu Q;Guo B;Ye F;Ge J;Xue L
脑源性神经营养因子（BDNF）已被证明在神经发育、可塑性和神经退行性疾病中起关键作用。BDNF在脑中的主要功能被广泛认为是突触调节。然而，BDNF如何调节突触传递，特别是突触前和突触后神经元之间的潜在信号级联，仍然存在争议。脑源性神经营养因子（BDNF）已被证明在神经发育、可塑性和神经退行性疾病中起关键作用。BDNF在脑中的主要功能被广泛认为是突触调节。然而，脑源性神经营养因子如何调节突触传递，特别是突触前和突触后神经元之间的潜在信号级联，仍然存在争议。在本研究中，我们研究了BDNF的行动，在大鼠萼型突触的任何性别的兴奋性突触后电流（EPSC）和突触前钙电流和电容的变化。我们发现BDNF通过激活突触前大麻素1型受体（CB 1 Rs）抑制EPSC、突触前钙内流和胞吐/胞吞作用。抑制CB 1 R可消除BDNF诱导的突触前抑制，而CB 1 R激动剂可模拟BDNF的作用。探索潜在的信号级联，我们发现BDNF特异性激活突触后TrkB受体，通过PLCγ/DGL通路诱导内源性大麻素的释放，并逆行激活突触前CB 1 R。我们还报道了AC/PKA参与调节囊泡内吞，这可能是BDNF诱导的钙依赖性和非依赖性内吞调节的原因。因此，我们的研究为生理和病理过程中BDNF/内源性大麻素相关的神经传递调节提供了新的见解。BDNF在调节突触强度中起关键作用。然而，BDNF如何调节突触传递及其潜在的信号级联仍然是一个谜。通过测量突触前电流和突触前钙电流及电容的变化，我们发现BDNF通过BDNF-TrkB-eCB信号通路抑制突触传递。突触后TrkB受体的激活通过PLCγ/DGL通路诱导内源性大麻素释放，逆行激活突触前CB 1 R，抑制AC/PKA，并抑制钙内流。我们的研究结果提供了一个全面的了解BDNF/内源性大麻素相关的神经元活动的调制。
Brain-derived neurotropic factor (BDNF) has been shown to play critical roles in neural development, plasticity, and neurodegenerative diseases. The main function of BDNF in the brain is widely accepted to be synaptic regulation. However, how BDNF modulates synaptic transmission, especially the underlying signaling cascades between presynaptic and postsynaptic neurons, remains controversial. Brain-derived neurotropic factor (BDNF) has been shown to play critical roles in neural development, plasticity, and neurodegenerative diseases. The main function of BDNF in the brain is widely accepted to be synaptic regulation. However, how BDNF modulates synaptic transmission, especially the underlying signaling cascades between presynaptic and postsynaptic neurons, remains controversial. In the present study, we investigated the actions of BDNF at rat calyx-type synapses of either sex by measuring the excitatory postsynaptic current (EPSC) and presynaptic calcium current and capacitance changes. We found that BDNF inhibits the EPSC, presynaptic calcium influx, and exocytosis/endocytosis via activation of the presynaptic cannabinoid Type 1 receptors (CB1Rs). Inhibition of the CB1Rs abolished the BDNF-induced presynaptic inhibition, whereas CB1R agonist mimicked the effect of BDNF. Exploring the underlying signaling cascade, we found that BDNF specifically activates the postsynaptic TrkB receptors, inducing the release of endocannabinoids via the PLCγ/DGL pathway and retrogradely activating presynaptic CB1Rs. We also reported the involvement of AC/PKA in modulating vesicle endocytosis, which may account for the BDNF-induced calcium-dependent and -independent regulation of endocytosis. Thus, our study provides new insights into the BDNF/endocannabinoid-associated modulation of neurotransmission in physiological and pathologic processes. SIGNIFICANCE STATEMENT BDNF plays critical roles in the modulation of synaptic strength. However, how BDNF regulates synaptic transmission and its underlying signaling cascade(s) remains elusive. By measuring EPSC and the presynaptic calcium current and capacitance changes at rat calyces, we found that BDNF inhibits synaptic transmission via BDNF-TrkB-eCB signaling pathway. Activation of postsynaptic TrkB receptors induces endocannabinoid release via the PLCγ/DGL pathway, retrogradely activating the presynaptic CB1Rs, inhibiting the AC/PKA, and suppressing calcium influx. Our findings provide a comprehensive understanding of BDNF/endocannabinoid-associated modulation of neuronal activities.