Neurotrophins are secreted proteins that control survival, differentiation, and synaptic plasticity. While mature neurotrophins regulate these functions via tyrosine kinase signaling (Trk), uncleaved pro-neurotrophins bind preferentially to the p75 neurotrophin receptor (p75NTR) and often exert opposite effects to those of mature neurotrophins. In the amygdala, brain-derived neurotrophic factor (BDNF) enables long-term potentiation as well as fear and fear extinction learning. In the present study, we focused on the impact of mature BDNF and proBDNF signaling on long-term depression (LTD) in the lateral amygdala (LA). Hence, we conducted extracellular field potential recordings in an in vitro slice preparation and recorded LTD in cortical and thalamic afferents to the LA. LTD was unchanged by acute block of BDNF/TrkB signaling. In contrast, LTD was inhibited by blocking p75NTR signaling, by disinhibition of the proteolytic cleavage of proBDNF into mature BDNF, and by preincubation with a function-blocking anti-proBDNF antibody. Since LTD-like processes in the amygdala are supposed to be related to fear extinction learning, we locally inhibited p75NTR signaling in the amygdala during or after fear extinction training, resulting in impaired fear extinction memory. Overall, these results suggest that in the amygdala proBDNF/p75NTR signaling plays a pivotal role in LTD and fear extinction learning.

中文翻译：

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LTD的ProBDNF依赖性和成年小鼠杏仁核的恐惧消退学习

神经营养因子是控制存活、分化和突触可塑性的分泌蛋白。虽然成熟的神经营养因子通过酪氨酸激酶信号 (Trk) 调节这些功能，但未切割的前神经营养因子优先与 p75 神经营养因子受体 (p75NTR) 结合，并且通常发挥与成熟神经营养因子相反的作用。在杏仁核中，脑源性神经营养因子 (BDNF) 可以实现长期增强以及恐惧和恐惧消退学习。在本研究中，我们专注于成熟 BDNF 和 proBDNF 信号传导对侧杏仁核 (LA) 长期抑郁症 (LTD) 的影响。因此，我们在体外切片制备中进行了细胞外场电位记录，并在皮质和丘脑传入 LA 中记录了 LTD。LTD 未因 BDNF/TrkB 信号传导的急性阻断而改变。相比之下，LTD 通过阻断 p75NTR 信号传导、解除 proBDNF 蛋白水解切割成成熟 BDNF 的抑制以及与功能阻断性抗 proBDNF 抗体预孵育而受到抑制。由于杏仁核中类似 LTD 的过程被认为与恐惧消退学习有关，我们在恐惧消退训练期间或之后局部抑制杏仁核中的 p75NTR 信号传导，导致恐惧消退记忆受损。总体而言，这些结果表明，在杏仁核中，proBDNF/p75NTR 信号传导在 LTD 和恐惧消退学习中起关键作用。我们在恐惧消退训练期间或之后局部抑制杏仁核中的 p75NTR 信号传导，导致恐惧消退记忆受损。总体而言，这些结果表明，在杏仁核中，proBDNF/p75NTR 信号传导在 LTD 和恐惧消退学习中起关键作用。我们在恐惧消退训练期间或之后局部抑制杏仁核中的 p75NTR 信号传导，导致恐惧消退记忆受损。总体而言，这些结果表明，在杏仁核中，proBDNF/p75NTR 信号传导在 LTD 和恐惧消退学习中起关键作用。