Cocaine Triggers Astrocyte-Mediated Synaptogenesis
| Autor: | Terry Chao, Junshi Wang, Yao Wang, Xiaojie Huang, Yan Dong, Lily E. Kramer, Susan R. Sesack, Masago Ishikawa, Hugh H. Huang, Eric J. Nestler, Oliver M. Schlüter, Avani Shukla, Ania Beroun, King-Lun Li, Yanhua H. Huang, Yao Q. Wang, Yue Yang, Noah D. Bastola |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Gene knockdown Synaptogenesis AMPA receptor Biology Nucleus accumbens Synapse 03 medical and health sciences Glutamatergic 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Silent synapse medicine Neuroscience 030217 neurology & neurosurgery Biological Psychiatry Astrocyte |
| Zdroj: | Biological Psychiatry. 89:386-397 |
| ISSN: | 0006-3223 |
| DOI: | 10.1016/j.biopsych.2020.08.012 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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