Shuang Qiu's group published in Biological Psychiatry on fear extinction

2023-03-03 Zhejiang University Pageviews: 39

The research team led by Prof. Shuang Qiu has recently published an article titled NMDAR-dependent synaptic potentiation via APPL1 signaling is required for the accessibility of a prefrontal neuronal assembly in retrieving fear extinction in Biological Psychiatry onFeb24th, Beijing time. This research identifies a cellular and molecular mechanism underlying fear extinction, which provides potential therapeutic targets to treat PTSD.

The ventromedial prefrontal cortex (vmPFC) has been viewed as a locus to store and recall extinction memory. However, the synaptic and cellular mechanisms underlying this process remain elusive. This research combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the vmPFC for fear extinction retrieval and found that both constitutive and conditional APPL1 knockout decreases NMDA receptor (NMDAR) function in the vmPFC and impairs fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduces NMDAR currents and disrupts extinction retrieval. This research further identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolishes NMDAR-dependent synaptic potentiation and disrupts extinction retrieval, while simultaneously chemogenetic activation of this ensemble rescues the impaired behaviors. Therefore, these results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons to retrieve extinction memory via controlling NMDAR-dependent potentiation.

Prof. Shuang Qiu from Zhejiang University School of Medicine is the main corresponding author. Pro. Yihui Cui from Zhejiang University School of Medicine is co-corresponding author. Dr. Shushan Hua, Jinjun Ding, Tiancheng Sun, and Chen Guo are the first authors. This work was supported by STI2030-Major Project, National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province, Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, National Key Research and Development Program of China, and Chinese Ministry of Education Project 111 Program.



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