Cocaine triggers glial-mediated synaptogenesis

Wang, J.; Li, K.-L.; Shukla, A.; Beroun, A.; Ishikawa, M.; Huang, X.; Wang, Y.; Wang, Y. Q.; Bastola, N. D.; Huang, H. H.; Kramer, L. E.; Chao, T.; Huang, Y. H.; Sesack, S. R.; Nestler, E. J.; Schluter, O. M.; Dong, Y.

doi:10.1101/2020.01.20.896233

bioRxiv · 10.1101/2020.01.20.896233

Cocaine triggers glial-mediated synaptogenesis

Wang, J.·Li, K.-L.·Shukla, A.·Beroun, A.·Ishikawa, M.·Huang, X.·Wang, Y.·Wang, Y. Q.·Bastola, N. D.·Huang, H. H.·Kramer, L. E.·Chao, T.·Huang, Y. H.·Sesack, S. R.·Nestler, E. J.·Schluter, O. M.·Dong, Y.

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Abstract

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, 2{delta}-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 (NAc). Specifically, cocaine administration activates NAc astrocytes, and preventing this activation blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of 2{delta}-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-2{delta}-1-mediated spinogenesis and silent synapse generation in the NAc occludes 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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Wang, J., Li, K.-L., Shukla, A., Beroun, A., Ishikawa, M., Huang, X., Wang, Y., Wang, Y. Q., Bastola, N. D., Huang, H. H., Kramer, L. E., Chao, T., Huang, Y. H., Sesack, S. R., Nestler, E. J., Schluter, O. M., Dong, Y.. 2020-01-20. Cocaine triggers glial-mediated synaptogenesis. https://doi.org/10.1101/2020.01.20.896233

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