The interaction of Synapsin 2a and Synaptogyrin-3 regulates fear extinction in mice
Xi-Ya Shen, Juan Zhang, He-Zhou Huang, Shao-Dan Li, Ling Zhou, Shi-Ping Wu, Cheng Tang, Xian Huang, Zhi-Qiang Liu, Zi-Yuan Guo, Xiang Li, Heng-Ye Man, You-Ming Lu, Ling-Qiang Zhu, Dan Liu
Xi-Ya Shen, Juan Zhang, He-Zhou Huang, Shao-Dan Li, Ling Zhou, Shi-Ping Wu, Cheng Tang, Xian Huang, Zhi-Qiang Liu, Zi-Yuan Guo, Xiang Li, Heng-Ye Man, You-Ming Lu, Ling-Qiang Zhu, Dan Liu
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Research Article Neuroscience

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

Abstract

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.

Authors

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

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Figure 7

Blocking the Syn2a/Syngr3 interaction by P-2A preserves presynaptic function and promotes fear extinction.

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Blocking the Syn2a/Syngr3 interaction by P-2A preserves presynaptic func...
(A) A diagram illustrates that P-2A disrupts the binding of Syn2a with Syngr3 in the presynapse. (B) The H293T cells were transfected with EGFP-Syn2a and HA-Syngr3 plasmids. After 24 hours, cells were treated with P-2A for 12 hours. Cell lysates were then collected for Co-IP assay. (C) WT mice were intraperitoneally injected with P-2A or S-2A. mPFC homogenates were collected and immunoprecipitated (IP) by using the anti-Syn2a. Representative immunoblots (upper) and quantification (lower) (n = 5 per group). (D) Representative Western blots (upper) and quantification (lower) of the protein levels of Syn2a and Syn2b in P-2A and S-2A treated mice (n = 3 replicates). (E) The mPFC lysates were precipitated with rabbit VAMP2 antibody, and probed with anti-Syntaxin and anti-SNAP25. (F) Quantitative analysis of Co-IP (n = 5–6 per group). (G) Representative traces (left) and quantification (right) of sEPSCs from BLA interneurons in P-2A or S-2A treated WT or Syn2a-E mice (n = 10 neurons from 3 mice per group). (H) Average freezing response for all trials during fear acquisition, extinction retrieval, and extinction of WT + S-2A, WT + P-2A, Syn2a-E + S-2A, and Syn2a-E + P-2A groups in mice (n = 5–8 per group). (I and J) Freezing response during the extinction training sessions (I) and testing sessions (J) of WT + S-2A, WT + P-2A, Syn2a-E + S-2A, and Syn2a-E + P-2A groups in mice (n = 5–8 per group). Statistical analyses among multiple groups were conducted using 1-way (F and G) or 2-way (H) ANOVA followed by Bonferroni post hoc tests, whereas an unpaired 2-tailed t test was conducted for comparing 2 groups (C, D, I, and J). *P< 0.05, **P < 0.01, ***P < 0.001. Values are presented as mean ± SEM.