Cytoplasmic FMR1-interacting protein 2 regulates cocaine reward by modulating synaptic plasticity in the nucleus accumbens

Abstract Cytoplasmic FMR1-interacting protein 2 (CYFIP2), consisting of the Wiskott–Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and synaptic plasticity. Mutating serine-968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice; however, the neuronal mechanisms underlying this response remain unknown. We performed cocaine reward-related behavioral tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc) using CYFIP2 S968F knock-in mice to investigate the role of CYFIP2 in regulating cocaine reward. Our findings revealed that CYFIP2 S968F attenuated cocaine-induced behavioral sensitization and conditioned place preference. Moreover, CYFIP2 S968F altered cocaine-associated CYFIP2 signaling, glutamatergic protein expression, and synaptic density following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the medial prefrontal cortex (mPFC) projecting to the NAc activity-mediating reward response, we assessed the optogenetic stimulation paradigm. Optogenetic activation of the NAc or mPFC-NAc pathway induced reward-related behaviors, and this effect was reversed by the S968F mutation in CYFIP2. These results suggest that CYFIP2 plays a role in controlling cocaine-mediated neuronal function and synaptic plasticity in the NAc and that CYFIP2 could serve as a target for regulating cocaine reward.