title: Functional interaction between BDNF and mGluR II in vitro: BDNF down-regulated mGluR II gene expression and an mGluR II agonist enhanced BDNF-induced BDNF gene expression in rat cerebral cortical neurons.
abstract: Accumulating evidence suggests functional interaction between brain-derived neurotrophic factor (BDNF) and metabotropic glutamate receptor (mGluR) signaling pathways in the central nervous system (CNS). To date, eight subtypes of mGluRs, mGluR1-8, have been identified, and a previous study suggested that BDNF leads to down-regulation of GluR2 mRNA in rat cerebral cortical cultures. However, precise transcriptomic effects of BDNF on other mGluRs and their cellular significance on the BDNF signaling pathway remain largely unknown. In this study, we assessed the transcriptomic effects of BDNF on mGluR1-8 in primary cultures of rat cerebral cortical neurons, and transcriptomic impacts of mGluR(s) whose expression is regulated by BDNF, on BDNF target genes. Real-time quantitative PCR (RT-qPCR) revealed that stimulation of the cultures with 100ng/mL BDNF led to marked reductions not only in the gene expression levels of mGluR2, but also in those of mGluR3, both of which belong to group II mGluRs (mGluR II). There were, on the other hand, no changes in the amounts of mGluR I (mGluR1 and 5) and III (mGluR4, 6, 7, and 8) mRNA. Further, 10ng/mL of BDNF, which mainly activates the high-affinity BDNF receptor, TrkB, but not the low-affinity receptor, p75NTR, was able to induce down-regulation of mGluR II mRNA. The BDNF-induced suppression of mGluR II was not significantly attenuated in the presence of tetrodotoxin (TTX), a blocker for voltage-gated sodium channels. In addition, on stimulation with BDNF (100ng/mL), no significant down-regulation of mGluR II mRNA was seen in cultured astrocytes, which only express the truncated form of TrkB. Finally, we assessed the transcriptomic effect of mGluR II on the expressions of BDNF target genes, BDNF and activity-regulated cytoskeleton-associated protein (Arc). LY404039, an mGluR II agonist, enhanced the BDNF-induced up-regulation of BDNF, but not Arc. On the other hand, LY341495, an mGluR II antagonist, down-regulated BDNF mRNA levels. Collectively, these observations demonstrated the detailed functional interaction between BDNF and mGluR II: Activation of mGluR II positively regulates self-induced BDNF expression, and, in turn, BDNF negatively regulates the gene expression of mGluR II in a neuronal activity-independent manner, in cortical neurons, but not in astrocytes.
authors.affiliation: Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University, Kagawa, Japan. Electronic address: ssuzukineurosci@gmail.com.
authors.forename: Shingo
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Japan Society for the Promotion of Science (JSPS), Tokyo, Japan; Bio-interface Research Group,Health Research Inst., National Institute of Advanced Industrial Science and Technology (AIST), Ikeda, Japan. Electronic address: h-koshimizu@umin.ac.jp.
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Koshimizu
authors.affiliation: Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Sanda, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Adachi
authors.affiliation: School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Hidetada
authors.initials: H
authors.lastname: Matsuoka
authors.affiliation: Department of Anesthesiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Fushimi
authors.affiliation: Department of Anesthesiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Ono
authors.affiliation: Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Ohta
authors.affiliation: Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Miki
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D005786:Gene Expression Regulation; D009474:Neurons / Q000378:metabolism*; D061251:Primary Cell Culture; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000096:biosynthesis; D020813:Receptor, trkB / Q000096:biosynthesis; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C104077:metabotropic glutamate receptor type 1; C000621230:Ntrk2 protein, rat; D020813:Receptor, trkB
keywords: BDNF; Cerebral cortical neurons; LY404039; mGluR II; mGluR2; mGluR3