神经科学
消光(光学矿物学)
基底外侧杏仁核
兴奋性突触后电位
抑制性突触后电位
边缘下皮质
生物
恐惧条件反射
扁桃形结构
心理学
药理学
前额叶皮质
认知
古生物学
作者
Xiya Shen,Juan Zhang,He-Zhou Huang,Shaodan Li,Luping Zhou,Shijie Wu,Cheng Tang,Xiner Huang,Zhiqiang Liu,Ziyuan Guo,Xiang Li,Heng‐Ye Man,Youming Lu,Ling‐Qiang Zhu,Dan Liu
摘要
The mechanisms behind a lack of efficient fear extinction in some individuals are unclear. Here, by employing a principal components analysis (PCA)-based approach, we differentiated the mice into extinction-resistant and susceptible groups. We identified that elevated synapsin 2a (Syn2a) in the infralimbic cortex (IL) to basolateral amygdala (BLA) circuit disrupted presynaptic orchestration, leading to an excitatory/inhibitory imbalance in the BLA region and causing extinction resistance. Overexpression or silencing of Syn2a levels in IL neurons replicated or alleviated behavioral, electrophysiological, and biochemical phenotypes in resistant mice. We further identified the proline-rich domain H in the C-terminal of Syn2a was indispensable for the interaction with synaptogyrin-3 (Syngr3) and demonstrated that disrupting this interaction restored extinction impairments. Molecular docking revealed ritonavir, an FDA-approved HIV drug, could disrupt Syn2a-Syngr3 binding and rescue fear extinction behavior in Syn2a-elevated mice. In summary, aberrant Syn2a elevation and its interaction with Syngr3 at the presynaptic site were crucial in fear extinction resistance, suggesting a potential therapeutic avenue for related disorders.
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