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Cocaine Triggers Astrocyte-Mediated Synaptogenesis
Biological Psychiatry ( IF 9.6 ) Pub Date : 2021-02-01 , DOI: 10.1016/j.biopsych.2020.08.012
Junshi Wang 1 , King-Lun Li 1 , Avani Shukla 2 , Ania Beroun 3 , Masago Ishikawa 1 , Xiaojie Huang 3 , Yao Wang 1 , Yao Q Wang 1 , Yue Yang 1 , Noah D Bastola 1 , Hugh H Huang 1 , Lily E Kramer 1 , Terry Chao 1 , Yanhua H Huang 4 , Susan R Sesack 5 , Eric J Nestler 6 , Oliver M Schlüter 7 , Yan Dong 5
Affiliation  

BACKGROUND Synaptogenesis is essential in forming new neurocircuits during development, and this is mediated in part by astrocyte-released thrombospondins (TSPs) and activation of their neuronal receptor, α2δ-1. Here, we show that this developmental synaptogenic mechanism is utilized during cocaine experience to induce spinogenesis and the generation of AMPA receptor-silent glutamatergic synapses in the adult nucleus accumbens shell (NAcSh). METHODS Using multidisciplinary approaches including astrocyte Ca2+ imaging, genetic mouse lines, viral-mediated gene transfer, and operant behavioral procedures, we monitor the response of NAcSh astrocytes to cocaine administration and examine the role of astrocytic TSP-α2δ-1 signaling in cocaine-induced silent synapse generation as well as the behavioral impact of astrocyte-mediated synaptogenesis and silent synapse generation. RESULTS Cocaine administration acutely increases Ca2+ events in NAcSh astrocytes, while decreasing astrocytic Ca2+ blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of α2δ-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-α2δ-1-mediated spinogenesis and synapse generation in NAcSh decreases cue-induced cocaine seeking after withdrawal from cocaine self-administration and cue-induced reinstatement of cocaine seeking after drug extinction. CONCLUSIONS These results establish that silent synapses are generated by an astrocyte-mediated synaptogenic mechanism in response to cocaine experience and embed critical cue-associated memory traces that promote cocaine relapse.

中文翻译:

可卡因触发星形胶质细胞介导的突触发生

背景突触发生对于在发育过程中形成新的神经回路至关重要,这部分是由星形胶质细胞释放的血小板反应蛋白 (TSP) 及其神经元受体 α2δ-1 的激活介导的。在这里,我们表明在可卡因体验期间利用这种发育性突触形成机制来诱导棘发生和成人伏隔核壳 (NAcSh) 中 AMPA 受体沉默谷氨酸能突触的产生。方法 使用多学科方法,包括星形胶质细胞 Ca2+ 成像、遗传小鼠系、病毒介导的基因转移和操作性行为程序,我们监测 NAcSh 星形胶质细胞对可卡因给药的反应,并检查星形胶质细胞 TSP-α2δ-1 信号传导在可卡因诱导的静默突触生成中的作用,以及星形胶质细胞介导的突触发生和静默突触生成的行为影响。结果 可卡因给药急剧增加 NAcSh 星形胶质细胞中的 Ca2+ 事件,同时减少星形胶质细胞 Ca2+ 阻断可卡因诱导的沉默突触的产生。此外,敲除 TSP2,或药理学抑制或病毒介导的 α2δ-1 敲除,可防止可卡因诱导的沉默突触的产生。此外,在 NAcSh 中破坏 TSP2-α2δ-1 介导的棘突生成和突触生成可减少线索诱导的可卡因在退出可卡因自我给药后的寻求和线索诱导的可卡因在药物灭绝后的恢复。
更新日期:2021-02-01
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