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eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons.

Placzek AN, Prisco GV, Khatiwada S, Sgritta M, Huang W, Krnjević K, Kaufman RJ, Dani JA, Walter P, Costa-Mattioli M. eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons. eLife e17517, 2016
(PMCID : PMC5154759) (PMID : 27960077) (PDF)

Abstract

Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1-an mRNA whose translation is controlled by p-eIF2α-in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP.


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