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Biol Psychiatry ; 89(4): 386-397, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33069367

RESUMEN

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.


Asunto(s)
Trastornos Relacionados con Cocaína , Cocaína , Animales , Astrocitos , Cocaína/farmacología , Ratones , Núcleo Accumbens , Ratas , Ratas Sprague-Dawley , Autoadministración , Sinapsis
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