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Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization

Nature Neuroscience volume 15, pages 1556–1562 (2012)Cite this article

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Abstract

Cocaine-induced alterations in synaptic glutamate function in nucleus accumbens are thought to mediate drug-related behaviors such as psychomotor sensitization. However, previous studies have examined global alterations in randomly selected accumbens neurons regardless of their activation state during cocaine-induced behavior. We recently found that a minority of strongly activated Fos-expressing accumbens neurons are necessary for cocaine-induced psychomotor sensitization, whereas the majority of accumbens neurons are less directly involved. We assessed synaptic alterations in these strongly activated accumbens neurons in Fos-GFP mice, which express a fusion protein of Fos and GFP in strongly activated neurons, and compared these alterations with those in surrounding non-activated neurons. Cocaine sensitization produced higher levels of 'silent synapses', which contained functional NMDA receptors and nonfunctional AMPA receptors only in GFP-positive neurons, 6–11 d after sensitization. Thus, distinct synaptic alterations are induced in the most strongly activated accumbens neurons that mediate psychomotor sensitization.

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Figure 1: Cocaine-induced GFP expression in nucleus accumbens.
Figure 2: Synaptic strength in activated nucleus accumbens neurons.
Figure 3: AMPAR subunit composition does not differ between GFP+ or GFP− neurons following cocaine test injections in repeated or acute cocaine mice.
Figure 4: Effects of bath-applied AMPA on GFP+ and GFP− accumbens neurons following cocaine test injections in repeated cocaine and acute cocaine mice.
Figure 5: Quantal sEPSC properties in GFP+ and GFP− accumbens neurons following cocaine test injections in repeated cocaine (GFP+, n = 21 cells from 15 mice; GFP−, n = 20 cells from 16 mice) and acute cocaine mice (GFP+, n = 24 cells from 15 mice; GFP−, n = 27 cells from 11 mice).
Figure 6: Higher levels of silent synapses were found on GFP+ neurons than on GFP− neurons following cocaine test injections in repeated cocaine, but not in acute cocaine mice.
Figure 7: The proportion of silent synapses from a randomly selected population of accumbens neurons, following 1–2-d or 6–11-d withdrawal from 3–5 d of repeated cocaine injections.
Figure 8: Silent synapses in GFP+ neurons from repeated cocaine mice (that is, mice challenged with cocaine following 6–11 d of withdrawal from repeated cocaine) were not associated with alterations in NR2B expression.

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Acknowledgements

We thank A. Barth for providing the first line of Fos-GFP mice, K. Knestaut and J. Hug for breeding the Fos-GFP mice, and E. Goldart and R. Ator for genotyping assistance. We thank S. Hall and T. Shippenberg for the use of their locomotor activity chambers. We thank S. Kourrich for many fruitful discussions regarding synaptic plasticity in the nucleus accumbens. This research was supported by the National Institute on Drug Abuse, Intramural Research Program.

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  1. Carl R Lupica and Bruce T Hope: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Health and Human Services, Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA

    Eisuke Koya, Fabio C Cruz, Robert Ator, Sam A Golden & Bruce T Hope

  2. Department of Health and Human Services, Electrophysiology Research Section, Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA

    Alexander F Hoffman & Carl R Lupica

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Contributions

E.K., F.C.C. and B.T.H. designed the behavioral experiments. E.K. performed these experiments with F.C.C., R.A., S.A.G. and B.T.H. E.K., A.F.H. and C.R.L. designed the electrophysiology experiments. C.R.L. designed and built the spinning disc confocal and electrophysiology apparatuses. E.K. conducted and analyzed the data from the behavior, immunohistochemistry and electrophysiology experiments. E.K., B.T.H. and C.R.L. wrote the paper.

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Correspondence to Bruce T Hope.

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Koya, E., Cruz, F., Ator, R. et al. Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization. Nat Neurosci 15, 1556–1562 (2012). https://doi.org/10.1038/nn.3232

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