Convergent dopamine and ALK4 signaling to PCBP1 controls FosB alternative splicing and cocaine behavioral sensitization

Abstract

ΔfosB is an alternatively spliced product of the FosB gene that is essential for dopamine‐induced reward pathways and that acts as a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown. Here, we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) via activation of the RNA‐binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon‐4 and intron‐4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co‐stimulation of D1 and ALK4 receptors. Finally, ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for ΔFosB generation and drug‐induced sensitization through convergent dopamine and ALK4 signaling. image The molecular and regulatory mechanisms underlying the generation of ΔFosB, an alternatively spliced FosB variant and an essential component of reward pathways and addiction are not well‐understood. Here, dopamine receptor signaling and the activin/ALK4/Smad3 pathway are found to synergistically control the generation of ΔFosB through activation of splicing regulator PCBP1. Concurrent dopamine and activin A signaling induces phosphorylation, nuclear translocation, and cooperative FosB mRNA intron binding of Smad3 and PCBP1. Activin A receptor ALK4 synergizes with dopamine D1 receptor to potentiate the generation and nuclear translocation of ∆FosB protein in medium spiny neurons (MSNs) of the nucleus accumbens (NAc). Ablation of either ALK4 or PCBP1 in MSNs impairs ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co‐stimulation of D1 and ALK4 receptors. Activin A expression is induced in microglial cells of the NAc upon repeated cocaine stimulation. ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine.