Department of Neurology, Alcohol Center for Translational Genetics, University of California San Francisco, CA 94143
We previously reported that excessive consumption of alcohol activates the H-Ras/PI3K/AKT signaling in the nucleus accumbens (NAc) of rodents, which ultimately leads to the activation of the mechanistic target of rapamycin complex 1 (mTORC1) (1-4). mTORC1 is localized in dendrites and plays an important role in synaptic plasticity by promoting the translation of synaptic proteins (5). We therefore hypothesized that mTORC1-dependent mRNA translation contributes to neuroadaptations that underlie excessive alcohol consumption. We utilized a biased approach in which we selected 8 candidate mRNAs whose translation has been reported to be controlled by mTORC1, and whose gene products contribute to plasticity, learning and memory, and an unbiased approach for which we utilized the high throughput RNA sequencing (RNA seq) approach. Rodents with a history of excessive alcohol consumption were sacrificed after the last drinking session, the NAc was dissected, and the levels of mRNAs undergoing translation were assessed in the polysomal RNA fraction. Among the identified gene products were collapsin response mediator protein-2 (CRMP-2) and ProSAP-interacting protein 1 (Prosapip1). Specifically, we showed that the translation but not the transcription of both CRMP-2 and Prosapip1 were induced in response to excessive alcohol drinking in an mTORC1-dependent manner. We further found that the corresponding increases in the protein levels of both CRMP-2 and Prosapip1 protein were detected in the synaptic fraction and were still maintained after 24 hours of withdrawal. We further showed that CRMP-2 and Prosapip1 play a major role in alcohol consumption and reward. Importantly, we report that CRMP-2 drives alcohol intake by increasing microtubules content, whereas Prosapip1 promotes the formation of actin filaments leading to changes in dendritic spine morphology in the Nac of alcohol consuming rodents. Together, our data suggest that alcohol-mediated mTORC1-dependent translation of CRMP-2 and Prosapip1 in the NAc leads to orchestrated changes in the synaptic structure that in turn drives the motivation to seek and consume alcohol.
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Supported by NIH-NIAAA P50 AA017072 (DR)