mTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors

作者：Liu, F.; Laguesse, S.; Legastelois, R.; Morisot, N.; Ben Hamida, S.; Ron, D.^*

来源：Molecular Psychiatry, 2017, 22(1): 89-101.

DOI：10.1038/mp.2016.12

• SYNAPTIC PLASTICITY
• MAMMALIAN TARGET
• STRUCTURAL PLASTICITY
• DORSOMEDIAL STRIATUM
• MESSENGER-RNA
• SIGNALING PATHWAY
• COMPLEX 1
• PHOSPHORYLATION
• MECHANISMS
• RECEPTOR

Mammalian target of rapamycin complex 1 (mTORC1) has an essential role in dendritic mRNA translation and participates in mechanisms underlying alcohol-drinking and reconsolidation of alcohol-related memories. Here, we report that excessive alcohol consumption increases the translation of downstream targets of mTORC1, including collapsin response mediator protein-2 (CRMP-2), in the nucleus accumbens (NAc) of rodents. We show that alcohol-mediated induction of CRMP-2 translation is mTORC1 dependent, leading to increased CRMP-2 protein levels. Furthermore, we demonstrate that alcohol intake also blocks glycogen synthase kinase-3 beta (GSK-3 beta)-phosphorylation of CRMP-2, which results in elevated binding of CRMP-2 to microtubules and a concomitant increase in microtubule content. Finally, we show that systemic administration of the CRMP-2 inhibitor lacosamide, or knockdown of CRMP-2 in the NAc decreases excessive alcohol intake. These results suggest that CRMP-2 in the NAc is a convergent point that receives inputs from two signaling pathways, mTORC1 and GSK-3 beta, that in turn drives excessive alcohol-drinking behaviors.

• 出版日期2017-1
• 单位中山大学