title: Transient domoic acid excitotoxicity increases BDNF expression and activates both MEK- and PKA-dependent neurogenesis in organotypic hippocampal slices.
abstract: BACKGROUND
  We have previously reported evidence of cell proliferation and increased neurogenesis in rat organotypic hippocampal slice cultures (OHSC) after a transient excitotoxic injury to the hippocampal CA1 area induced by low concentrations of the AMPA/kainate agonist domoic acid (DOM). An increased baseline rate of neurogenesis may contribute to recovery from DOM-induced mild injury but the intracellular mechanism(s) responsible for neuronal proliferation remain unclear. The current study investigated the key intracellular pathways responsible for DOM-induced neurogenesis in OHSC including the effects of transient excitotoxicity on the expression of brain-derived neurotrophic factor (BDNF), a well-known regulator of progenitor cell mitosis.
  
  
  RESULTS
  Application of a low concentration of DOM (2 μM) for 24 h followed by recovery induced a significant and long lasting increase in BDNF protein levels expressed by both neurons and microglial cells. Furthermore, the mild DOM toxicity stimulated both PKA and MEK-dependent intracellular signaling cascades and induced a significant increase in BDNF- transcription factor CREB activation and BDNF-receptor TrkB expression. Coexposure to specific inhibitors of PKA and MEK phosphorylation resulted in a significant decrease in the neurogenic marker doublecortin.
  
  
  CONCLUSIONS
  Our results suggest that transient excitotoxic insult induced by DOM produces BDNF and CREB overexpression via MEK and PKA pathways and that both pathways mediate, at least in part, the increased neural proliferation resulting from mild excitotoxicity.
authors.affiliation: Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, PEI, Canada.
authors.forename: Anabel
authors.initials: A
authors.lastname: Pérez-Gómez
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Tasker
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D000089662:Doublecortin Protein; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D039481:CD11b Antigen; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D050882:CREB-Binding Protein; D020813:Receptor, trkB; D017868:Cyclic AMP-Dependent Protein Kinases; D020930:MAP Kinase Kinase Kinases; C012301:domoic acid; D007608:Kainic Acid