title: Homeostatic NMDA receptor down-regulation via brain derived neurotrophic factor and nitric oxide-dependent signalling in cortical but not in hippocampal neurons.
abstract: Nitric oxide (NO) has been proposed to down-regulate NMDA receptors (NMDA-Rs) in a homeostatic manner. However, NMDA-R-dependent NO synthesis also can cause excitotoxic cell death. Using bicuculline-stimulated hippocampal and cortical cell cultures, we have addressed the role of the brain-derived neurotrophic factor-NO pathway in NMDA-R down-regulation. This pathway protected cortical cells from NMDA-induced death and led to NMDA-R inhibition. In contrast, no evidence was gained for the presence of this protective pathway in hippocampal neurons, in which NMDA-induced NO synthesis was confirmed to be toxic. Therefore, opposing effects of NO depended on the activation of different signalling pathways. The pathophysiological relevance of this observation was investigated in synaptosomes and post-synaptic densities isolated from rat hippocampi and cerebral cortices following kainic acid-induced status epilepticus. In cortical, but not in hippocampal synaptosomes, brain-derived neurotrophic factor induced NO synthesis and inhibited NMDA-R currents present in isolated post-synaptic densities. In conclusion, we identified a NO-dependent homeostatic response in the rat cerebral cortex induced by elevated activity. A low performance of this pathway in brain areas including the hippocampus may be related to their selective vulnerability in pathologies such as temporal lobe epilepsy.
authors.affiliation: Laboratorio de Neurotoxicología Ambiental, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Sandoval
authors.forename: Andrés
authors.initials: A
authors.lastname: González
authors.forename: Ariel
authors.initials: A
authors.lastname: Caviedes
authors.forename: Floria
authors.initials: F
authors.lastname: Pancetti
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Smalla
authors.forename: Thilo
authors.initials: T
authors.lastname: Kaehne
authors.forename: Luis
authors.initials: L
authors.lastname: Michea
authors.forename: Eckart D
authors.initials: ED
authors.lastname: Gundelfinger
authors.forename: Ursula
authors.initials: U
authors.lastname: Wyneken
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007814:Larva; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013574:Synaptosomes; D014981:Xenopus
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001120:Arginine; D006162:Guanylate Cyclase; D002118:Calcium; D001640:Bicuculline