Archival ReportSAR405, a Highly Specific VPS34 Inhibitor, Disrupts Auditory Fear Memory Consolidation of Mice via Facilitation of Inhibitory Neurotransmission in Basolateral Amygdala
Section snippets
Animals
Male C57BL/6 mice used in the present study were obtained from Hunan Silaike Jingda Laboratory Animal Corporation Ltd (Changsha, China). They were maintained on a 12-hour light/dark cycle at a constant temperature (22 ± 2°C) and humidity of 50 ± 10% with food and water available ad libitum. Five mice were housed in a cage, and mice 8 to 11 weeks of age were used in the experiment. All experimental procedures were approved by the Animal Welfare Committee of Huazhong University of Science and
Infusion of SAR405 Into BLA Impairs Long-Term Memory and Inhibits Autophagy Induced by Auditory Fear Conditioning
First, we explored whether SAR405 had an effect on auditory fear conditioning. Mice implanted with a bilateral guide cannula aimed at the BLA were administered with SAR405 (1 μM) after recovering from surgery, as shown in Figure 1A. These mice were subjected to auditory fear conditioning 24 hours after administration. Fear memory was evaluated by measuring the percentage of freezing behavior at 3 hours (short-term memory [STM]) and 24 hours (long-term memory [LTM]) after training to investigate
Discussion
The present study demonstrated that SAR405, as a specific autophagy inhibitor, impaired memory consolidation through blocking the autophagy-dependent downregulation of the surface GABAAR γ2 subunit, and the increased GABARAP-GABAAR binding was required for autophagic degradation of surface GABAARs (Figure 6). These observations uncovered a novel role of autophagy pathway in learning and memory, and propose SAR405 as a new candidate for prevention of psychiatric disorders with altered fear
Acknowledgments and Disclosures
This work was supported by Foundation for Innovative Research Groups of National Natural Science Foundation of China Grant No. 81721005 to (J-GC and FW); National Basic Research Program of China Grant No. 2014CB744601 (to FW); National Natural Science Foundation of China Grant Nos. 81471377 (to FW), 81671438 (to FW), 81473198 (to J-GC), 81673414 (to J-GC); Program for Changjiang Scholars and Innovative Research Team in University Grant No. IRT13016 (to J-GC); and the Program for Huazhong
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KL and H-SC contributed equally to this work.