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

• Published in: The Journal of biological chemistry 2018-10, Vol.293 (40), p.15641-15651
• Main Authors: Zhang, Wenping, Shi, Yuqiang, Peng, Yanxi, Zhong, Ling, Zhu, Shuang, Zhang, Wenbo, Tang, Shao-Jun
• Format: Article
• Language: English
• Subjects: Animals; Anti-Anxiety Agents - pharmacology; Azepines - pharmacology; Benzamides - pharmacology; beta Catenin - genetics; beta Catenin - metabolism; beta-catenin (B-catenin); brain-derived neurotrophic factor (BDNF); 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; Gene Expression Regulation; Hindlimb; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurobiology; neuron; Neuronal Plasticity - physiology; Neurons - drug effects; Neurons - metabolism; pain; 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; synapse; Transcription, Genetic; Wnt signaling; Wnt Signaling Pathway; Wnt3A Protein - genetics; Wnt3A Protein - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.002840

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.