Calcium‐permeable <scp>AMPA</scp> receptors and silent synapses in cocaine‐conditioned place preference

<jats:title>Abstract</jats:title><jats:p>Exposure to cocaine generates silent synapses in the nucleus accumbens (<jats:styled-content style="fixed-case">NA</jats:styled-content>c), whose eventual unsilencing/maturation by recruitment of calcium‐permeable <jats:styled-content style="fixed-case">AMPA</jats:styled-content>‐type glutamate receptors (<jats:styled-content style="fixed-case">CP</jats:styled-content>‐<jats:styled-content style="fixed-case">AMPAR</jats:styled-content>s) after drug withdrawal results in profound remodeling of <jats:styled-content style="fixed-case">NA</jats:styled-content>c neuro‐circuits. Silent synapse‐based <jats:styled-content style="fixed-case">NA</jats:styled-content>c 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 <jats:styled-content style="fixed-case">PSD</jats:styled-content>‐93, <jats:styled-content style="fixed-case">PSD</jats:styled-content>‐95, and <jats:styled-content style="fixed-case">SAP</jats:styled-content>102 differentially regulate excitatory synapse properties in the <jats:styled-content style="fixed-case">NA</jats:styled-content>c. 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 <jats:styled-content style="fixed-case">NA</jats:styled-content>c silent synapse maturation in cocaine‐conditioned place preference (<jats:styled-content style="fixed-case">CPP</jats:styled-content>). Wild‐type and knockout mice alike all acquired cocaine‐<jats:styled-content style="fixed-case">CPP</jats:styled-content> and exhibited increased levels of silent synapses after drug‐context conditioning. However, the mice differed in <jats:styled-content style="fixed-case">CPP</jats:styled-content> retention and <jats:styled-content style="fixed-case">CP</jats:styled-content>‐<jats:styled-content style="fixed-case">AMPAR</jats:styled-content> incorporation. Collectively, our results indicate that <jats:styled-content style="fixed-case">CP</jats:styled-content>‐<jats:styled-content style="fixed-case">AMPAR</jats:styled-content>‐mediated maturation of silent synapses in the <jats:styled-content style="fixed-case">NA</jats:styled-content>c is a signature of drug–context association, but this maturation is not required for establishing or retaining cocaine‐<jats:styled-content style="fixed-case">CPP</jats:styled-content>.</jats:p>