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EMBO J. 2017 Feb 15;36(4):458-474. doi: 10.15252/embj.201695465. Epub 2017 Jan 11.

Calcium-permeable AMPA receptors and silent synapses in cocaine-conditioned place preference.

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Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany.
Cluster of Excellence "Nanoscale Microscopy and Molecular Physiology of the Brain", University Medical Center, Göttingen, Germany.
Göttingen Graduate School for Neurosciences and Molecular Biosciences, Göttingen, Germany.
Laboratory of Neurobiology, The Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland.
Genes to Cognition Programme, Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
Department of Psychology, Arizona State University, Tempe, AZ, USA.
Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA


Exposure to cocaine generates silent synapses in the nucleus accumbens (NAc), whose eventual unsilencing/maturation by recruitment of calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) after drug withdrawal results in profound remodeling of NAc neuro-circuits. Silent synapse-based NAc remodeling was shown to be critical for several drug-induced behaviors, but its role in acquisition and retention of the association between drug rewarding effects and drug-associated contexts has remained unclear. Here, we find that the postsynaptic proteins PSD-93, PSD-95, and SAP102 differentially regulate excitatory synapse properties in the NAc. Mice deficient for either of these scaffold proteins exhibit distinct maturation patterns of silent synapses and thus provided instructive animal models to examine the role of NAc silent synapse maturation in cocaine-conditioned place preference (CPP). Wild-type and knockout mice alike all acquired cocaine-CPP and exhibited increased levels of silent synapses after drug-context conditioning. However, the mice differed in CPP retention and CP-AMPAR incorporation. Collectively, our results indicate that CP-AMPAR-mediated maturation of silent synapses in the NAc is a signature of drug-context association, but this maturation is not required for establishing or retaining cocaine-CPP.


AMPA receptor; cocaine; conditioned place preference; nucleus accumbens; silent synapse

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