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24 Dec 2019


Retrieval-Driven Hippocampal NPTX2 Plasticity Facilitates the Extinction of Cocaine-Associated Context Memory


Fudan researchers have discovered the role of NPTX2 in the extinction of cocaine-associated context memory. NPTX2 has been known as a neuronal immediate early gene (IEG) belonging to a member of the neuronal pentraxin family. The research was published in Biological Psychiatry on December 10.

Recruitment of GluA1-containing AMPAR on the neuronal membrane accelerates the extinction of cocaine-associated context memory after retrieval

Drug addiction is considered a disorder of aberrant learningand memory. The environmental cues, strongly associatedwith the rewarding effects of the drug, trigger craving andrelapse. Previous studies have shown that immediately after retrieval by associative cues, the consolidated memory destabilizes and requires gene expression to be restabilized, which is a cascade of events that ultimately lead to the renewal, strengthening or extinction of the memory. However, the molecular basis of this process remains largely unknown.

In a cocaine conditioned place preference (CPP) paradigm, researchers used the ribosomal tagging (Ribo Tag) strategy, which separated ribosome-associated mRNA, to measure the translational state of pyramidal neurons in the dorsal hippocampus of the mice at different time points after the retrieval of cocaine-associated context memory. Bioinformatics analysis revealed the signaling pathways related to the dopaminergic and synaptic plasticity were most actively translated one hour after retrieval, with Nptx2 as the hub gene of synaptic remodeling.

Accordingly, knockdown of Nptx2 in dorsal hippocampus impairs the acquisition of cocaine CPP, while its upregulation facilitates the extinction of cocaine-associated context memory. Further research has shown that NPTX2 causes excitatory synaptic transmission by recruiting GluA1-containing AMPA receptor (AMPAR) on the neuronal membrane to accelerate the extinction of cocaine-associated context memory. In addition, NPTX2 protein synthesis in the hippocampal neurons increases significantly one hour after retrieval, accompanied by enhanced excitatory synaptic transmission. The NPTX2-mediated plasticity in retrieval-activated neurons is required for the extinction of cocaine-associated context memory, indicating that NPTX2 might be a potential target for the treatment of cue-induced cocaine seeking.

PhD candidates Wang Zhilin and Jin Tao, and associate researcher Le Qiumin at the School of Medical Sciences are the first authors, with Professor Ma Lan and Professor Wang Feifei being the corresponding authors.


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