Dynorphin up-regulation in the dentate granule cell mossy fiber pathway following chronic inhibition of GluN2B-containing NMDAR is associated with increased CREB (Ser 133) phosphorylation, but is independent of BDNF/TrkB signaling pathways.
Emerging evidence suggests that neuronal responses to N-methyl-d-aspartate (NMDAR) activation/inactivation are influenced by subunit composition. For example, activation of synaptic NMDAR (comprised of GluN2A>GluN2B) phosphorylates cAMP-response-element-binding protein (CREB) at Ser 133, induces BDNF expression and promotes neuronal survival. Activation of extrasynaptic NMDAR (comprised of GluN2B>GluN2) dephosphorylates CREB (Ser 133), reduces BDNF expression and triggers neuronal death. These results led us to hypothesize that chronic inhibition of GluN2B-containing NMDAR would increase CREB (Ser 133) phosphorylation, increase BDNF levels and subsequently alter downstream dynorphin (DYN) and neuropeptide Y (NPY) expression. We focused on DYN and NPY because these neuropeptides can decrease excitatory neurotransmission and seizure occurrence and we reported previously that seizure-like events are reduced following chronic treatment with GluN2B antagonists. Consistent with our hypothesis, chronic treatment (17-21days) of hippocampal slice cultures with the GluN2B-selective antagonists ifenprodil or Ro25,6981 increased both CREB (Ser 133) phosphorylation and granule cell mossy fiber pathway DYN expression. Similar treatment with the non-subtype-selective NMDAR antagonists d-APV or memantine had no significant effect on either CREB (Ser 133) phosphorylation or DYN expression. In contrast to our hypothesis, BDNF levels were decreased following chronic treatment with Ro25,6981, but not ifenprodil, d-APV or memantine. Blockade of BDNF actions and TrkB activation did not significantly augment hilar DYN expression in vehicle-treated cultures and had no effect in Ro25,6981 treated cultures. These findings suggest that chronic exposure to GluN2B-selective NMDAR antagonists increased DYN expression through a putatively pCREB-dependent, but BDNF/TrkB-independent mechanism.
Department of Pharmacology, Uniformed Services University School of Medicine, Bethesda, MD 20814, United States.
W Bradley
WB
Rittase
Department of Pharmacology, Uniformed Services University School of Medicine, Bethesda, MD 20814, United States.
Yu
Y
Dong
Department of Pharmacology, Uniformed Services University School of Medicine, Bethesda, MD 20814, United States.
DaRel
D
Barksdale
Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Bethesda, MD 20814, United States.
Zygmunt
Z
Galdzicki
Department of Pharmacology, Uniformed Services University School of Medicine, Bethesda, MD 20814, United States. Electronic address: suzanne.bausch@usuhs.edu.
Suzanne B
SB
Bausch
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism*; D008559:Memantine / Q000494:pharmacology; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; C121001:NR2B NMDA receptor; D009478:Neuropeptide Y; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D004399:Dynorphins; D015763:2-Amino-5-phosphonovalerate; D020813:Receptor, trkB; C010739:ifenprodil; D008559:Memantine
Hippocampus; Ifenprodil; Memantine; N-methyl-d-aspartate; Neuropeptide Y