| First Author | Wang J | Year | 2021 |
| Journal | Biol Psychiatry | Volume | 89 |
| Issue | 4 | Pages | 386-397 |
| PubMed ID | 33069367 | Mgi Jnum | J:336934 |
| Mgi Id | MGI:6741573 | Doi | 10.1016/j.biopsych.2020.08.012 |
| Citation | Wang J, et al. (2021) Cocaine Triggers Astrocyte-Mediated Synaptogenesis. Biol Psychiatry 89(4):386-397 |
| abstractText | 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, alpha2delta-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 Ca(2+) 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-alpha2delta-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 Ca(2+) events in NAcSh astrocytes, while decreasing astrocytic Ca(2+) blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of alpha2delta-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-alpha2delta-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. |
