| First Author | Hua SS | Year | 2023 |
| Journal | Biol Psychiatry | Volume | 94 |
| Issue | 3 | Pages | 262-277 |
| PubMed ID | 36842495 | Mgi Jnum | J:340743 |
| Mgi Id | MGI:7465940 | Doi | 10.1016/j.biopsych.2023.02.013 |
| Citation | Hua SS, et al. (2023) NMDAR-dependent synaptic potentiation via APPL1 signaling is required for the accessibility of a prefrontal neuronal assembly in retrieving fear extinction. Biol Psychiatry |
| abstractText | BACKGROUND: 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. METHODS: We 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. RESULTS: We 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. We 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. CONCLUSIONS: Therefore, our 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. |
