GluN2B-mediated regulation of silent synapses for receptor specification and addiction memory

Psychostimulants, including cocaine, elicit stereotyped, addictive behaviors. The reemergence of silent synapses containing only NMDA-type glutamate receptors is a critical mediator of addiction memory and seeking behaviors. Despite the predominant abundance of GluN2B-containing NMDA-type glutamate receptors in silent synapses, their operational mechanisms are not fully understood. Here, using conditional depletion/deletion of GluN2B in D1-expressing accumbal medium spiny neurons, we examined the synaptic and behavioral actions that silent synapses incur after repeated exposure to cocaine. GluN2B ablation reduces the proportion of silent synapses, but some of them can persist by substitution with GluN2C, which drives the aberrantly facilitated synaptic incorporation of calcium-impermeable AMPA-type glutamate receptors (AMPARs). The resulting precocious maturation of silent synapses impairs addiction memory but increases locomotor activity, both of which can be normalized by the blockade of calcium-impermeable AMPAR trafficking. Collectively, GluN2B supports the competence of cocaine-induced silent synapses to specify the subunit composition of AMPARs and thereby the expression of addiction memory and related behaviors. Cocaine creates ‘silent synapses’, immature brain connections lacking AMPA receptors. Researchers studied mice with GluN2B, a key protein in these synapses, which was selectively removed from specific brain cells. Using genetic tools and electrophysiology, they found that GluN2B removal reduced silent synapses and weakened drug-related memory but unexpectedly increased drug sensitivity. The findings suggest that the removal of GluN2B leads to fewer silent synapses but GluN2B aids in their maturation by adding calcium-insensitive AMPA receptors. This highlights GluN2B’s crucial role in maintaining silent synapses, providing new insights into addiction memory and potential treatment strategies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.