Cocaine Triggers Astrocyte-Mediated Synaptogenesis

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...

Full description

Saved in:
Bibliographic Details
Published in:Biological psychiatry (1969) 2021-02, Vol.89 (4), p.386-397
Main Authors: Wang, Junshi, Li, King-Lun, Shukla, Avani, Beroun, Ania, Ishikawa, Masago, Huang, Xiaojie, Wang, Yao, Wang, Yao Q., Yang, Yue, Bastola, Noah D., Huang, Hugh H., Kramer, Lily E., Chao, Terry, Huang, Yanhua H., Sesack, Susan R., Nestler, Eric J., Schlüter, Oliver M., Dong, Yan
Format: Article
Language:English
Subjects:
Accumbens
Animals
Astrocyte
Astrocytes
Cocaine
Cocaine - pharmacology
Cocaine-Related Disorders
Mice
Nucleus Accumbens
Rats
Rats, Sprague-Dawley
Self Administration
Silent synapse
Synapses
Synaptogenesis
Thrombospondin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 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. 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.
ISSN:0006-3223
1873-2402
DOI:10.1016/j.biopsych.2020.08.012