Prosapip1, a new target for alcohol

We previously reported that excessive consumption of alcohol activates the mechanistic target of rapamycin complex 1 (mTORC1) in the nucleus accumbens (NAc) of rodents. mTORC1 is an important transducer of local dendritic translation that participates in learning and memory processes as well as in mechanisms underlying alcohol-drinking behaviors. Using an unbiased RNAseq approach, we identified Prosapip1 as a novel downstream target of mTORC1 whose translation (but not transcription) and consequent protein expression are increased in the NAc of mice excessively consuming alcohol. We next showed that the increase in Prosapip1 protein levels in response to alcohol drinking was localized to the synaptic fraction and was maintained even after 24 hours of withdrawal. Prosapip1 levels were not altered in brain regions where mTORC1 is not activated by alcohol. We further demonstrated that Prosapip1 overexpression in the NAc as well as binge drinking of alcohol promote the formation of actin filaments, whereas shRNA-mediated knockdown of endogenous Prosapip1 reduces the F-actin amount. These changes in actin dynamics lead to Prosapip1-dependent dendritic spine morphological changes in the NAc of alcohol consuming mice, with enlarged spine head size and increased proportion of mushroom-type spines. Finally, we determined whether Prosapip1 contributes to mechanisms underlying alcohol drinking behaviors. We found that Prosapip1 knockdown in the NAc leads to an attenuation of operant self-administration of alcohol and reduces alcohol place preference. Together, our data suggest that Prosapip1 is a new target of mTORC1and a molecular gateway to excessive alcohol use that drives morphological plasticity changes in the NAc underlying alcohol drinking and reward.