The interaction of Synapsin 2a and Synaptogyrin-3 regulates fear extinction in mice
Xi-Ya Shen, … , Ling-Qiang Zhu, Dan Liu
Xi-Ya Shen, … , Ling-Qiang Zhu, Dan Liu
Published January 4, 2024
Citation Information: J Clin Invest. 2024;134(4):e172802. https://doi.org/10.1172/JCI172802.
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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 1

Presynaptic inhibition of the IL-BLA circuit disrupts the E/I balance in the BLA of EXT-R mice.

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Presynaptic inhibition of the IL-BLA circuit disrupts the E/I balance in...
(A) A schematic illustration of the fear memory extinction paradigm. (B) PCA plot of freezing times of 40 adult C57BL/6J mice during the extinction testing trials. (C) Representative confocal images of c-Fos staining in the amygdala for control, NO-EXT, EXT-S, and EXT-R mice. Scale bar: 100 μm. (D) The quantification of the number of c-Fos+ neurons in different brain regions of control, NO-EXT, EXT-S, and EXT-R mice (n = 3 mice per group). (E) Representative sEPSC and sIPSC traces recorded from EXT-S and EXT-R pyramidal neurons in the BLA. (F) Quantifications of frequencies and amplitudes of sEPSC and sIPSC. (G) Quantification of E/I ratios (sEPSC frequency × amplitude/ sIPSC frequency × amplitude) (n = 10 neurons from 3 mice per group). (H) Representative sEPSC traces recorded in BLA interneurons of EXT-S and EXT-R mice and the quantitative analysis (n = 10 neurons from 3 mice per group). (I) Representative photographs of ChR2-EYFP fluorescence at the viral IL injection site (upper) and ChR2-EYFP expressing afferent IL axon in the BLA (lower). (J) Paired-pulse ratios obtained from blue light–evoked excitatory postsynaptic current (EPSC) amplitudes reveal increased facilitation in EXT-R when compared with EXT-S mice. n = 10 cells (from 3 mice) per group. Statistical analyses among multiple groups were conducted using 1-way (D) or 2-way ANOVA (F) followed by Bonferroni post hoc tests, whereas an unpaired 2-tailed t test was conducted for comparing 2 groups (G, H, and J). *P < 0.05, **P < 0.01, and ***P < 0.001. Values are presented as mean ± SEM.