Journal Article

The interaction of Synapsin 2a and Synaptogyrin-3 regulates fear extinction in mice

Shen, Xi-Ya, Li, Shao-Dan, Huang, He-Zhou, Zhou, Ling, Huang, Xian, Liu, Zhi-Qiang, Liu, Dan, Man, Heng-Ye, Zhang, Juan, Tang, Cheng, Lu, You-Ming, Wu, Shi-Ping, Zhu, Ling-Qiang, Li, Xiang, Guo, Zi-Yuan

2024

Overview

The mechanisms behind a lack of efficient fear extinction in some individuals are unclear. Here, by employing a principal components analysis-based approach, we differentiated the mice into extinction-resistant and susceptible groups. We determined 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 that the proline-rich domain H in the C-terminus of Syn2a was indispensable for the interaction with synaptogyrin-3 (Syngr3) and demonstrated that disrupting this interaction restored extinction impairments. Molecular docking revealed that ritonavir, an FDA-approved HIV drug, could disrupt Syn2a-Syngr3 binding and rescue fear extinction behavior in Syn2a-elevated mice. In summary, the aberrant elevation of Syn2a expression and its interaction with Syngr3 at the presynaptic site were crucial in fear extinction resistance, suggesting a potential therapeutic avenue for related disorders.

• Publisher: American Society for Clinical Investigation
• Subject: Amygdala / Animals / Antiretroviral drugs / Anxiety / Brain / C-Terminus / Development and progression / Drug approval / Extinction (Learning) / Extinction behavior / Extinction, Psychological - physiology / Fear / Fear - physiology / Fear conditioning / Health aspects / HIV / Human immunodeficiency virus / Medical research / Membrane proteins / Memory / Mice / Molecular Docking Simulation / Neurons / Neuroscience / Phenotypes / Phosphoproteins / Physiological aspects / Post traumatic stress disorder / Prefrontal Cortex - metabolism / Principal components analysis / Ritonavir / Synapsin / Synapsins - genetics / Synapsins - metabolism / Synaptic vesicles / Synaptogyrins - metabolism