Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors

Cell Rep. 2019 Dec 3;29(10):3235-3252.e9. doi: 10.1016/j.celrep.2019.10.116.

Abstract

Dopamine (DA) activates mitogen-activated protein kinase (MAPK) via protein kinase A (PKA)/Rap1 in medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R) in the nucleus accumbens (NAc), thereby regulating reward-related behavior. However, how MAPK regulates reward-related learning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we perform proteomic analysis using affinity beads coated with cyclic AMP response element binding protein (CREB)-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identify more than 400 CBP-interacting proteins, including Neuronal Per Arnt Sim domain protein 4 (Npas4). We find that MAPK phosphorylates Npas4 downstream of PKA, increasing the Npas4-CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. The deletion of Npas4 in D1R-expressing MSNs impairs cocaine-induced place preference, which is rescued by Npas4-wild-type (WT), but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases transcriptional activity to enhance reward-related learning and memory.

Keywords: Behavior; CBP; Dopamine; Gene expression; Learning; MAPK; Memory; Npas4; Phosphorylation; Reward.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Brain-Derived Neurotrophic Factor / metabolism
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Cocaine / pharmacology
  • Dopamine / metabolism
  • Female
  • Gene Expression / drug effects
  • Gene Expression / physiology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation / drug effects
  • Phosphorylation / physiology*
  • Proteomics / methods
  • Receptors, Dopamine D1 / metabolism
  • Reward
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Brain-Derived Neurotrophic Factor
  • Npas4 protein, mouse
  • Receptors, Dopamine D1
  • Mitogen-Activated Protein Kinases
  • Cocaine
  • Dopamine