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.
Various cocaine‐induced behaviors are linked to generation and remodeling of silent synapses in the nucleus accumbens. Postsynaptic signaling scaffold proteins PSD‐93, PSD‐95, and SAP102 differentially affect the properties of such excitatory synapses as well as the acquisition and retention of drug reward/context association in mice.
Increased expression of GluA2‐lacking calcium‐permeable AMPA receptor in medium spiny neurons of the nucleus accumbens is a signature for drug–context association.
Mice deficient for either PSD‐93, PSD‐95, or SAP102 exhibit distinct maturation patterns of cocaine‐induced silent synapses.
Incorporation of calcium‐permeable AMPA receptor into silent synapses is not required for retention of cocaine‐conditioned place preference.
The EMBO Journal (2017) 36: 458–474
- Received August 11, 2016.
- Revision received November 4, 2016.
- Accepted December 12, 2016.
- © 2017 The Authors
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