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Research Articles, Behavioral/Cognitive

AMPA and NMDA Receptor Trafficking at Cocaine-Generated Synapses

Yao Q. Wang, Yanhua H. Huang, Saju Balakrishnan, Lidong Liu, Yu Tian Wang, Eric J. Nestler, Oliver M. Schlüter and Yan Dong
Journal of Neuroscience 3 March 2021, 41 (9) 1996-2011; DOI: https://doi.org/10.1523/JNEUROSCI.1918-20.2021
Yao Q. Wang
1Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
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Yanhua H. Huang
2Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
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Saju Balakrishnan
3Department of Psychiatry and Psychotherapy, University Medical Center, 37075 Göttingen, Germany
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Lidong Liu
4Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia V6T 1Z3, Canada
5Department of Medicine, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
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Yu Tian Wang
4Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia V6T 1Z3, Canada
5Department of Medicine, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
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Eric J. Nestler
6Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029
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Oliver M. Schlüter
1Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
3Department of Psychiatry and Psychotherapy, University Medical Center, 37075 Göttingen, Germany
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Yan Dong
1Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
2Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
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Abstract

Cocaine experience generates AMPA receptor (AMPAR)-silent synapses in the nucleus accumbens (NAc), which are thought to be new synaptic contacts enriched in GluN2B-containing NMDA receptors (NMDARs). After drug withdrawal, some of these synapses mature by recruiting AMPARs, strengthening the newly established synaptic transmission. Silent synapse generation and maturation are two consecutive cellular steps through which NAc circuits are profoundly remodeled to promote cue-induced cocaine seeking after drug withdrawal. However, the basic cellular processes that mediate these two critical steps remains underexplored. Using a combination of electrophysiology, viral-mediated gene transfer, and confocal imaging in male rats as well as knock-in (KI) mice of both sexes, our current study characterized the dynamic roles played by AMPARs and NMDARs in generation and maturation of silent synapses on NAc medium spiny neurons after cocaine self-administration and withdrawal. We report that cocaine-induced generation of silent synapses not only required synaptic insertion of GluN2B-containing NMDARs, but also, counterintuitively, involved insertion of AMPARs, which subsequently internalized, resulting in the AMPAR-silent state on withdrawal day 1. Furthermore, GluN2B NMDARs functioned to maintain these cocaine-generated synapses in the AMPAR-silent state during drug withdrawal, until they were replaced by nonGluN2B NMDARs, a switch that allowed AMPAR recruitment and maturation of silent synapses. These results reveal dynamic interactions between AMPARs and NMDARs during the generation and maturation of silent synapses after cocaine experience and provide a mechanistic basis through which new synaptic contacts and possibly new neural network patterns created by these synapses can be manipulated for therapeutic benefit.

SIGNIFICANCE STATEMENT Studies over the past decade reveal a critical role of AMPA receptor-silent, NMDA receptor-containing synapses in forming cocaine-related memories that drive cocaine relapse. However, it remains incompletely understood how AMPA and NMDA receptors traffic at these synapses during their generation and maturation. The current study characterizes a two-step AMPA receptor trafficking cascade that contributes to the generation of silent synapses in response to cocaine experience, and a two-step NMDA receptor trafficking cascade that contributes to the maturation of these synapses after cocaine withdrawal. These results depict a highly regulated cellular procedure through which nascent glutamatergic synapses are generated in the adult brain after drug experience and provide significant insight into the roles of glutamate receptors in synapse formation and maturation.

  • AMPA receptor
  • cocaine
  • NMDA receptor
  • nucleus accumbens
  • silent synapses
  • trafficking

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The Journal of Neuroscience: 41 (9)
Journal of Neuroscience
Vol. 41, Issue 9
3 Mar 2021
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AMPA and NMDA Receptor Trafficking at Cocaine-Generated Synapses
Yao Q. Wang, Yanhua H. Huang, Saju Balakrishnan, Lidong Liu, Yu Tian Wang, Eric J. Nestler, Oliver M. Schlüter, Yan Dong
Journal of Neuroscience 3 March 2021, 41 (9) 1996-2011; DOI: 10.1523/JNEUROSCI.1918-20.2021

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AMPA and NMDA Receptor Trafficking at Cocaine-Generated Synapses
Yao Q. Wang, Yanhua H. Huang, Saju Balakrishnan, Lidong Liu, Yu Tian Wang, Eric J. Nestler, Oliver M. Schlüter, Yan Dong
Journal of Neuroscience 3 March 2021, 41 (9) 1996-2011; DOI: 10.1523/JNEUROSCI.1918-20.2021
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Keywords

  • AMPA receptor
  • cocaine
  • NMDA receptor
  • nucleus accumbens
  • silent synapses
  • trafficking

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