PMID- 23865384 OWN - NLM STAT- MEDLINE DCOM- 20131101 LR - 20211203 IS - 1471-2202 (Electronic) IS - 1471-2202 (Linking) VI - 14 DP - 2013 Jul 17 TI - Transient domoic acid excitotoxicity increases BDNF expression and activates both MEK- and PKA-dependent neurogenesis in organotypic hippocampal slices. PG - 72 LID - 10.1186/1471-2202-14-72 [doi] AB - 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 muM) 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. FAU - Perez-Gomez, Anabel AU - Perez-Gomez A AD - Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, PEI, Canada. FAU - Tasker, R Andrew AU - Tasker RA LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130717 PL - England TA - BMC Neurosci JT - BMC neuroscience JID - 100966986 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (CD11b Antigen) RN - 0 (Dcx protein, rat) RN - 0 (Doublecortin Protein) RN - 0 (Enzyme Inhibitors) RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Neurotoxins) RN - EC 2.3.1.48 (CREB-Binding Protein) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) RN - M02525818H (domoic acid) RN - SIV03811UC (Kainic Acid) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - CD11b Antigen/metabolism MH - CREB-Binding Protein/metabolism MH - Cyclic AMP-Dependent Protein Kinases/*metabolism MH - Doublecortin Protein MH - Drug Interactions MH - Enzyme Inhibitors/pharmacology MH - Glial Fibrillary Acidic Protein/metabolism MH - Hippocampus/*drug effects MH - Kainic Acid/*analogs & derivatives/pharmacology MH - MAP Kinase Kinase Kinases/*metabolism MH - Neurogenesis/*drug effects MH - Neurotoxins/*pharmacology MH - Organ Culture Techniques MH - Rats MH - Receptor, trkB/metabolism MH - Signal Transduction/drug effects MH - Time Factors PMC - PMC3722092 EDAT- 2013/07/20 06:00 MHDA- 2013/11/02 06:00 PMCR- 2013/07/17 CRDT- 2013/07/20 06:00 PHST- 2013/01/03 00:00 [received] PHST- 2013/07/12 00:00 [accepted] PHST- 2013/07/20 06:00 [entrez] PHST- 2013/07/20 06:00 [pubmed] PHST- 2013/11/02 06:00 [medline] PHST- 2013/07/17 00:00 [pmc-release] AID - 1471-2202-14-72 [pii] AID - 10.1186/1471-2202-14-72 [doi] PST - epublish SO - BMC Neurosci. 2013 Jul 17;14:72. doi: 10.1186/1471-2202-14-72.