SYNCRIP controls miR-137 and striatal learning in animal models of methamphetamine abstinence  

作　　者：Baeksun Kim Sung Hyun Tag Eunjoo Nam Suji Ham Sujin Ahn Juhwan Kim Doo-Wan Cho Sangjoon Lee Young-Su Yang Seung Eun Lee Yong Sik Kim Il-Joo Cho Kwang Pyo Kim Su-Cheol Han Heh-In Im 

机构地区：[1]Convergence Research Center for Diagnosis,Treatment and Care System of Dementia(DTC),Korea Institute of Science and Technology(KIST),Seoul 02792,Republic of Korea [2]Division of Bio-Medical Science&Technology,KIST School,Korea University of Science and Technology(UST),Seoul 02792,Republic of Korea [3]Center for Neuroscience,KIST,Seoul 02792,Republic of Korea [4]Animal Model Research Center,Jeonbuk Department of Inhalation Research,Korea Institute of Toxicology(KIT),Korea Research Institute of Chemical Technology(KRICT),Jeongeup 56212,Republic of Korea [5]Research Animal Resource Center,KIST,Seoul 02792,Republic of Korea [6]Department of Pharmacology,Seoul National University College of Medicine,Seoul 03080,Republic of Korea [7]Center for BioMicrosystems,KIST,Seoul 02792,Republic of Korea [8]Department of Applied Chemistry,Kyung Hee University,Gyeonggi-do 17104,Republic of Korea

出　　处：《Acta Pharmaceutica Sinica B》2022年第8期3281-3297,共17页药学学报（英文版）

基　　金：funded by Korea Institute of Science and Technology Intramural Funding (2E26640,2E30952;Republic of Korea);National Research Council of Science & Technology (NST) grant by Korean government (MSIP) (CRC-15-04-KIST;Republic of Korea);Center for Women In Science,Engineering,and Technology (WISET) grant by Korean government (WISET2020-525;Republic of Korea);National Research Foundation of Korea (2017R1A2B2003993,2020R1A2C2004610;Republic of Korea);UST Young Scientist Research Program through Korea University of Science and Technology (UST) (2017YS03;Republic of Korea)。

摘　　要：Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome.Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA-target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine(MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR,LC-MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome.

关 键 词：METHAMPHETAMINE ABSTINENCE WITHDRAWAL STRIATUM miR-137 SYNCRIP Biomarker Behavior 

分 类 号：R749.64[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]