SAR405, a Highly Specific VPS34 Inhibitor, Disrupts Auditory Fear Memory Consolidation of Mice via Facilitation of Inhibitory Neurotransmission in Basolateral Amygdala
SAR405, a Highly Specific VPS34 Inhibitor, Disrupts Auditory Fear Memory Consolidation of Mice via Facilitation of Inhibitory Neurotransmission in Basolateral Amygdala
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SAR405 是一种高度特异性的 VPS34 抑制剂，通过促进基底外侧杏仁核的抑制性神经传递来破坏小鼠的听觉恐惧记忆巩固。
DOI：
10.1016/j.biopsych.2018.07.026
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发表时间：
2019-02-01
影响因子：
10.6
通讯作者：
Wang, Fang
中科院分区：
文献类型：
--
作者：
Li, Kuan;Chen, Hong-Sheng;Wang, Fang
背景：自噬已被证明在记忆缺陷以及神经递质受体的降解中发挥重要作用。 SAR405是一种新发现的抑制剂，可以特异性抑制液泡分选蛋白34并阻止自噬体生物发生。然而，SAR405对记忆过程的影响仍然很大程度上未知。方法：使用蛋白质印迹、免疫荧光和透射电子显微镜来评估恐惧条件反射和SAR405治疗后的自噬水平。使用行为测试、生物素化测定、电生理学和免疫共沉淀来揭示 SAR405 在记忆巩固中的机制。结果：SAR405 注入基底外侧杏仁核通过自噬抑制损害长期记忆。此外，SAR405 扰乱了恐惧条件反射后γ-氨基丁酸 A 型受体 (GABAAR) 的运输，SAR405 也逆转了恐惧条件反射诱导的微型抑制性突触后电流的频率和幅度降低，表明 SAR405 通过阻断基底外侧杏仁核中下调的抑制性神经传递来破坏记忆巩固。研究发现，GABA(A)R 相关蛋白 (GABARAP) 及其与 GABAAR g2 亚基的相互作用在恐惧条件反射后上调，而 SAR405 可以抑制这种增加的相互作用。此外，反式激活转录激活剂 GABARAP 抑制肽破坏 GABARAP-GABA(A)R 结合，可阻止 GABA(A)R 表面表达的减少，从而减弱长期记忆。结论：本研究表明，SAR405 可以通过干预自噬和 GABA(A)R 运输来防止记忆巩固，并对以夸大恐惧记忆为特征的疾病具有潜在的治疗价值，例如创伤后应激障碍。
BACKGROUND: Autophagy has been demonstrated to play an important role in memory deficits as well as the degradation of neurotransmitter receptors. SAR405 is a newly discovered inhibitor that can specifically inhibit vacuolar sorting protein 34 and prevent autophagosome biogenesis. However, the effects of SAR405 on memory processes remain largely unknown.METHODS: Western blotting, immunofluorescence, and transmission electron microscopy were used to assess the level of autophagy after fear conditioning and SAR405 treatment. Behavioral tests, biotinylation assay, electrophysiology, and co-immunoprecipitation were used to unravel the mechanisms of SAR405 in memory consolidation.RESULTS: SAR405 infusion into the basolateral amygdala impaired long-term memory through autophagy inhibition. Furthermore, the trafficking of gamma-aminobutyric acid type A receptors (GABAARs) following fear conditioning was disrupted by SAR405, and the decreased frequency and amplitude of miniature inhibitory postsynaptic currents induced by fear conditioning were also reversed by SAR405, suggesting that SAR405 disrupted memory consolidation through blockade of the downregulated inhibitory neurotransmission in basolateral amygdala. GABA(A)R-associated protein (GABARAP) and its interaction with GABAAR g2 subunit were found to be upregulated after fear conditioning, and SAR405 could suppress this increased interaction. Moreover, disruption of the GABARAP-GABA(A)R binding by a trans-activating transcriptional activator-GABARAP inhibitory peptide blocked the decrease in surface expression of GABA(A)Rs and attenuated long-term memory.CONCLUSIONS: The present study suggests that SAR405 can prevent the memory consolidation via intervening autophagy and GABA(A)R trafficking and has a potential therapeutic value for disorders characterized by exaggerated fear memories, such as posttraumatic stress disorder.