Cocaine Triggers Astrocyte-Mediated Synaptogenesis.
Cocaine Triggers Astrocyte-Mediated Synaptogenesis.
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DOI：
10.1016/j.biopsych.2020.08.012
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发表时间：
2021-02-15
影响因子：
10.6
通讯作者：
Dong Y
中科院分区：
文献类型：
--
作者：
Wang J;Li KL;Shukla A;Beroun A;Ishikawa M;Huang X;Wang Y;Wang YQ;Yang Y;Bastola ND;Huang HH;Kramer LE;Chao T;Huang YH;Sesack SR;Nestler EJ;Schlüter OM;Dong Y
突触发生是在发育过程中形成新的神经回路所必需的，这在一定程度上是由星形胶质细胞释放的血栓反应蛋白(TSP)及其神经元受体α2δ−1的激活所介导的。在这里，我们证明了在可卡因刺激期间，这种发育中的突触发生机制被用来诱导脊髓发生和成人伏隔核壳(NAcSh)中AMPA受体沉默的谷氨酸能突触的产生。我们利用星形胶质细胞钙离子成像、小鼠遗传学、病毒介导的基因转移和可操作的行为程序等多学科方法，监测NAcSh星形胶质细胞对可卡因注射的反应，研究星形胶质细胞TSP-α2δ−1信号在可卡因诱导的无声突触产生中的作用，以及星形胶质细胞介导的突触发生和沉默突触产生的行为影响。给予可卡因可显著增加NAcSh星形胶质细胞中的钙事件，而减少星形胶质细胞中的钙离子则阻断可卡因诱导的沉默突触的产生。此外，TSP2的敲除，或药物抑制或病毒介导的α2δ−1的敲除，都可以阻止可卡因诱导的沉默突触的产生。此外，干扰Tsp2-α2δ−1介导的脊髓发生和突触生成可减少戒断后线索诱导的可卡因寻找和戒毒后线索诱导的可卡因寻找的恢复。这些结果表明，无声突触是由星形胶质细胞介导的突触生成机制对可卡因体验做出反应，并嵌入促进可卡因复发的关键线索相关记忆痕迹。
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). 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, examine the role of astrocytic TSP-α2δ−1 signaling in cocaine-induced silent synapse generation, and behavioral impact of astrocyte-mediated synaptogenesis and silent synapse generation. 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. 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.
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影响因子：
64.8
作者：
Attardo A;Fitzgerald JE;Schnitzer MJ
通讯作者：
Schnitzer MJ
影响因子：
34.7
作者：
Clarke, Laura E.;Barres, Ben A.
通讯作者：
Barres, Ben A.
影响因子：
2.5
作者：
IRUELAARISPE, ML;LISKA, DJ;BORNSTEIN, P
通讯作者：
BORNSTEIN, P
DOI：
10.1177/1073858415579405
发表时间：
2015-10
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Huang YH;Schlüter OM;Dong Y
通讯作者：
Dong Y
影响因子：
64.8
作者：
Golden SA;Heshmati M;Flanigan M;Christoffel DJ;Guise K;Pfau ML;Aleyasin H;Menard C;Zhang H;Hodes GE;Bregman D;Khibnik L;Tai J;Rebusi N;Krawitz B;Chaudhury D;Walsh JJ;Han MH;Shapiro ML;Russo SJ
通讯作者：
Russo SJ