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 4

IL-BLA circuit–specific Syn2a overexpression induces E/I imbalance in the BLA of EXT-R mice.

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IL-BLA circuit–specific Syn2a overexpression induces E/I imbalance in th...
(A) A schematic illustration of the virus-induced dual-cre-loxp system to overexpress Syn2a specifically in the IL-BLA circuit. (B) Top, starter cells (yellow) in the BLA (colabeling of red [RV] and green [helper viruses]). Bottom, RV-labeled neurons in IL colocalized with the overexpressed Syn2a (green). Scale bar: 100 μm. (C) Average freezing response for all trials during fear acquisition, extinction retrieval, and extinction of IL-BLA OE-2a and control mice. (D and E) Freezing response during the extinction training sessions (D) and testing sessions (E) of IL-BLA OE-2a and control mice (n = 6 per group). (F) Representative traces of sEPSCs from BLA interneurons infected with control or IL-BLA OE-2a virus at IL. (G) Average data show that the frequency and amplitude of sEPSCs of BLA interneurons in IL-BLA OE-2a mice compared with control mice (n = 10 neurons from 3 mice per group). (H) Representative sEPSC and sIPSC traces recorded from PBS-injected and CNO-injected mice pyramidal neurons in BLA (n = 10 neurons from 3 mice per group). (I) Quantifications of frequencies and amplitudes of sEPSC and sIPSC and E/I ratios. (J) Average freezing response for all trials during fear acquisition and fear extinction retrieval and extinction of PBS- or CNO-injected mice (n = 6 per group). (K and L) Freezing response during the extinction training sessions (K) and testing sessions (L) of PBS- or CNO-injected mice (n = 6 per group). Statistical analyses among multiple groups were conducted using 2-way ANOVA followed by Bonferroni post hoc tests (C, I, and J), whereas an unpaired 2-tailed t test was conducted for comparing 2 groups (D, E, G, K, and L). *P < 0.05, **P < 0.01, and ***P < 0.001. Values are presented as mean ± SEM.