Neuron activity-induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit

J Biol Chem. 2018 Oct 5;293(40):15641-15651. doi: 10.1074/jbc.RA118.002840. Epub 2018 Aug 23.

Abstract

Brain-derived neurotrophic factor (BDNF) is a master regulator of synaptic plasticity in various neural circuits of the mammalian central nervous system. Neuron activity-induced BDNF gene expression is regulated through the Ca2+/CREB pathway, but other regulatory factors may also be involved in controlling BDNF levels. We report here that Wnt/β-catenin signaling plays a key role in controlling neuron activity-regulated BDNF expression. Using primary cortical cultures, we show that blockade of Wnt/β-catenin signaling inhibits the BDNF up-regulation that is induced by activation of the N-methyl-d-aspartic acid (NMDA) receptor and that activation of the Wnt/β-catenin signaling pathway stimulates BDNF expression. In vivo, Wnt/β-catenin signaling activated BDNF expression and was required for peripheral pain-induced up-regulation of BDNF in the mouse spine. We also found that conditional deletion of one copy of either Wntless (Wls) or β-catenin by Nestin-Cre-mediated recombination is sufficient to inhibit the pain-induced up-regulation of BDNF. We further show that the Wnt/β-catenin/BDNF axis in the spinal neural circuit plays an important role in regulating capsaicin-induced pain. These results indicate that neuron activity-induced Wnt signaling stimulates BDNF expression in the pain neural circuits. We propose that pain-induced Wnt secretion may provide an additional mechanism for intercellular coordination of BDNF expression in the neural circuit.

Keywords: Wnt signaling; beta-catenin (B-catenin); brain-derived neurotrophic factor (BDNF); gene expression; neuron; pain; synapse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Azepines / pharmacology
  • Benzamides / pharmacology
  • Brain-Derived Neurotrophic Factor / agonists
  • Brain-Derived Neurotrophic Factor / genetics*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Capsaicin / administration & dosage
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Embryo, Mammalian
  • Gene Expression Regulation
  • Hindlimb
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity / physiology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Pain / chemically induced
  • Pain / drug therapy
  • Pain / genetics*
  • Pain / physiopathology
  • Primary Cell Culture
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / physiopathology
  • Transcription, Genetic
  • Wnt Signaling Pathway
  • Wnt3A Protein / genetics*
  • Wnt3A Protein / metabolism
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • ANA 12 compound
  • Anti-Anxiety Agents
  • Azepines
  • Bdnf protein, mouse
  • Benzamides
  • Brain-Derived Neurotrophic Factor
  • CTNNB1 protein, mouse
  • Gpr177 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Receptors, G-Protein-Coupled
  • Receptors, N-Methyl-D-Aspartate
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin
  • Capsaicin