Dopamine-induced phosphorylation of NPAS4 through MAPK regulates reward-related learning and memory

Abstract

Dopamine (DA) type 1 receptor (D1R) signaling activates cAMP/PKA and then activates MAPK through Rap1 in striatal medium spiny neurons (MSNs) and plays a pivotal role in regulating neuronal excitability and reward-related behaviors. However, how D1R signaling regulates reward-related learning and memory through the gene expression is not fully understood. To isolate and concentrate the transcriptional factors (TFs) regulated by D1R signaling in mouse striatum, we performed proteomic analyses using affinity beads coated with CREB-binding protein (CBP), which acts as co-activator of numerous TFs and is involved in reward-related learning and memory. We identified Neuronal Per Arnt Sim domain protein 4 (NPAS4), as a novel CBP-interacting protein in striatum. NPAS4 was phosphorylated by MAPK downstream of the D1R. The phosphorylation of NPAS4 increased the interaction of NPAS4 with CBP and enhanced the BDNF exon I and IV promoter activity. Furthermore, the deletion of NPAS4 in accumbal D1R-expressing MSNs impaired the cocaine-induced place preference. The deficit in cocaine-induced place preference in NPAS4 deletion was restored by co-transfection with NPAS4-WT but not phospho-deficient mutant of NPAS4. These results suggest that MAPK phosphorylates NPAS4 downstream of D1R and increases its binding with CBP, thereby regulating BDNF expression and reward-related learning and memory.