title: Enhanced mossy fiber sprouting and synapse formation in organotypic hippocampal cultures following transient domoic acid excitotoxicity.
abstract: We have previously reported evidence of BDNF upregulation 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 receptor agonist domoic acid (DOM). The changes observed in OHSC were consistent with observations in vivo, where low concentrations of DOM administered to rats during perinatal development caused increased BDNF and TrkB expression in the resulting adult animals. The in vivo low dose-DOM treatment also results in permanent alterations in hippocampal structure and function, including abnormal formation of dentate granule cell axons projecting to area CA3 (mossy fiber sprouting). Our objective in the current study is to determine if low concentrations of DOM induce mossy fiber sprouting and/or synaptogenesis in OHSC in order to facilitate future studies on the mechanisms of structural hippocampal plasticity induced by DOM. We report herein that application of a low concentration of DOM (2 μM) for 24 h followed by recovery induced a significant increase in the expression of the mossy fiber marker ZnT3 that progressed over time in culture. The DOM insult (2 μM, 24 h) also resulted in a significant upregulation of both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. All of the observed effects were fully antagonized by co-administration of the AMPA/kainate antagonists CNQX or NBQX but only partly by the NMDA antagonist CPP and not by the calcium channel blocker nifedipine. We conclude that exposure of OHSC to concentrations of DOM below those required to induce permanent neurotoxicity can induce a progressive change in hippocampal structure that can effectively model DOM effects in vivo.
authors.affiliation: Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE, C1A 4P3, 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; D015220:Calcium Channels / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D027682:Cation Transport Proteins; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D007608:Kainic Acid; D008565:Membrane Proteins; D009498:Neurotoxins; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; C501449:Dlg4 protein, rat; C569016:Syp protein, rat; C503697:zinc transporter 3, rat; C012301:domoic acid