State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai, P.R. China 200438.
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai, P.R. China 200438
J Neurosci. 2020 Oct 14;40(42):8070-8087. doi: 10.1523/JNEUROSCI.2838-19.2020. Epub 2020 Sep 18.
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. 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.
脑源性神经营养因子 (BDNF) 在神经发育、可塑性和神经退行性疾病中发挥着关键作用。BDNF 在大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，特别是在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，我们通过测量兴奋性突触后电流 (EPSC) 和突触前钙电流和电容变化，研究了 BDNF 在雄性和雌性大鼠钟型突触中的作用。我们发现 BDNF 通过激活突触前大麻素 1 型受体 (CB1Rs) 抑制 EPSC、突触前钙内流和胞吐/胞吞作用。抑制 CB1Rs 消除了 BDNF 诱导的突触前抑制，而 CB1R 激动剂模拟了 BDNF 的作用。在探索潜在的信号级联时，我们发现 BDNF 特异性激活突触后 TrkB 受体，通过 PLCγ/DGL 途径释放内源性大麻素，并逆行激活突触前 CB1Rs。我们还报告了 AC/PKA 在调节囊泡胞吞作用中的作用，这可能解释了 BDNF 诱导的钙依赖性和非依赖性胞吞作用调节。因此，我们的研究为 BDNF/内源性大麻素相关的神经传递在生理和病理过程中的调节提供了新的见解。BDNF 在调节突触强度方面起着关键作用。然而，BDNF 如何调节突触传递及其潜在的信号级联仍然难以捉摸。通过测量大鼠钟型结构的 EPSC 和突触前钙电流和电容变化，我们发现 BDNF 通过 BDNF-TrkB-eCB 信号通路抑制突触传递。激活突触后 TrkB 受体通过 PLCγ/DGL 途径诱导内源性大麻素释放，逆行激活突触前 CB1Rs，抑制 AC/PKA，并抑制钙内流。我们的发现提供了对 BDNF/内源性大麻素相关神经元活动调节的全面理解。
