Nptx2 Facilitates Cocaine-Contextual Memory Extinction Via Recruiting GluA1-AMPAR in Dorsal Hippocampus

The extinction of a learned response requires acquisition of new information and would be expected to require protein synthesis, yet it remains unclear which genes are controlled and how they are regulated to allow extinction to neutralize learned behavior. Here, we explored the temporal molecular changes that occur after extinction learning in hippocampal CA3-CA1 by RiboTag, and discovered the specific translational regulation of genes and pathways during cocaine-contexture memory extinction. Data mining by WGCNA (weighted gene co-expression network analysis) revealed Nptx2 (Neuronal activity-regulated pentraxin), involved in experience-dependent synaptic plasticity, as the hub gene upregulated by extinction. Down regulating Nptx2 in dorsal hippocampus (dHP) impaired cocaine-contexture memory extinction, as well as extinction-driven synaptic remodeling in dorsal CA1. While overexpressing Nptx2 promoted cocaine-contexture memory extinction. In addition, overexpressing the Nptx2 pentraxin (PTX) domain, which mediates their binding to AMPARs, enhanced the memory extinction and excitatory synaptic transmission, while the enhancement could be abolished by inhibiting the membrane trafficking of AMPARs. Furthermore, Nptx2 in cocaine contexture-reactivated neurons of dHP was required for the cocaine-contexture memory extinction. These data indicate that the extinction dependent upregulation of Nptx2 contributes to extinction-driven synaptic remodeling and facilitates learning of a cue formerly associated with reward becomes associated with a new consequence (no reward).