Dopamine and ALK4 signaling synergize to induce PCBP1-mediated alternative splicing of FosB and sustained behavioral sensitization to cocaine

Abstract

{Delta}FosB, an alternative spliced product of FosB, is an essential component of dopamine-induced reward pathways and 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 {Delta}FosB mRNA in medium spiny neurons (MSNs) of the nucleus-accumbens (NAc) through 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 {Delta}FosB mRNA induction and nuclear translocation of {Delta}FosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Importantly, ALK4 was required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for {Delta}FosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.