Sprouting of mossy fibers and the vacating of postsynaptic targets in the inner molecular layer of the dentate gyrus.
Aberrant mossy fiber sprouting, which presumably results from hilar mossy cell death after status epilepticus (SE), is a frequently studied feature of temporal lobe epilepsy. Although mossy fiber sprouting can be suppressed by the protein synthesis inhibitor cycloheximide, spontaneous seizures remain unaltered. We have investigated the mechanisms underlying the ability of cycloheximide to block SE-induced mossy fiber sprouting in the inner molecular layer of dentate gyrus (IML). Pilocarpine-induced SE in the presence of cycloheximide resulted in a reduced number of injured hilar cells compared to rats not pretreated with cycloheximide. Presumed mossy cells, identified by calcitonin gene related peptide (CGRP) immunohistochemistry, were not significantly reduced in either group 60 days after SE. Whereas controls had a strong band of CGRP-positive fibers (putative mossy cell axons) and no neo-Timm stained fibers in the IML, pilocarpine-treated rats had no CGRP fibers and strong neo-Timm staining. Cycloheximide-pilocarpine-treated animals, in contrast, had CGRP and neo-Timm staining similar to controls. Cycloheximide might protect hilar CGRP-positive cells during SE and, by allowing those cells to retain their normal axonal projection, prevent mossy fiber sprouting. The recently suggested "irritable" mossy cell hypothesis relies on the survival of mossy cells for network hyperexcitability. We hypothesized that CGRP may be a marker for a subpopulation of relatively resistant mossy cells in rats, which, if they survive injury, may become irritable and contribute to hyperexcitability. We suggest that cycloheximide prevents SE-induced mossy fiber sprouting by preventing the loss of hilar CGRP-positive cells (putative mossy cells).
Longo
Beatriz
B
Department of Physiology, UNIFESP-EPM, R. Botucatu, 862, CEP 04023-062, São Paulo, Brazil.
Covolan
Luciene
L
Chadi
Gerson
G
Mello
Luiz Eugênio A M
LE
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018721:Muscarinic Agonists; D010862:Pilocarpine; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D013569:Synapses / Q000187:drug effects / Q000473:pathology*
D018721:Muscarinic Agonists; D011500:Protein Synthesis Inhibitors; D010862:Pilocarpine; D003513:Cycloheximide; D015740:Calcitonin Gene-Related Peptide