title: Increased excitability and molecular changes in adult rats after a febrile seizure.
abstract: Both early life inflammation and prolonged febrile seizures have been associated with increased excitation in the adult brain. We hypothesized this may be due in part to changes in the cation-chloride cotransporter system. Rat pups received saline or lipopolysaccharide/kainic acid (LPS/KA) resulting in inflammation, followed by a behavioral febrile seizure (FS) in approximately 50% of rats. Adult animals from the saline, inflammation, or inflammation + FS groups underwent the following: (1) in vitro electrophysiologic studies; (2) Western blotting or polymerase chain reaction; or (3) application of the Na-K-Cl cotransporter 1 (NKCC1) blocker bumetanide to determine its effect on reversing increased excitability in vitro. The inflammation and inflammation + FS groups demonstrated increased excitability in vitro and increased hippocampal protein expression of NR2B and GABAA α5 receptor subunits and mRNA expression of NKCC1. The inflammation + FS group also had decreased protein expression of GluR2 and GABAA α1 receptor subunits and mRNA and protein expression of KCC2. Bumetanide decreased in vitro 4-aminopyridine-induced inter-ictal activity in the inflammation and inflammation + FS groups. The results demonstrate early-life inflammation with or without a behavioral FS can lead to long-lasting molecular changes and increased excitability in the adult rat hippocampus, although some changes are more extensive when inflammation is accompanied by behavioral seizure activity. Bumetanide is effective in reversing increased excitability in vitro, providing evidence for a causal role for cation-chloride cotransporters and suggesting this drug may prove useful for treating epilepsy that develops after a FS.
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. areid@ucalgary.ca
authors.forename: Aylin Y
authors.initials: AY
authors.lastname: Reid
authors.forename: Kiarash
authors.initials: K
authors.lastname: Riazi
authors.forename: G
authors.initials: G
authors.lastname: Campbell Teskey
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Pittman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002034:Bumetanide / Q000627:therapeutic use; D004232:Diuretics / Q000627:therapeutic use; D018690:Excitatory Amino Acid Agonists; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid; D008070:Lipopolysaccharides; D008297:Male; D011247:Pregnancy; D051381:Rats; D020318:Rats, Long-Evans; D060888:Real-Time Polymerase Chain Reaction; D003294:Seizures, Febrile / Q000139:chemically induced / Q000378:metabolism* / Q000523:psychology*; D028021:Sodium-Potassium-Chloride Symporters / Q000187:drug effects; D064506:Solute Carrier Family 12, Member 2
chemical_list: D004232:Diuretics; D018690:Excitatory Amino Acid Agonists; D008070:Lipopolysaccharides; C578879:Slc12a2 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D007608:Kainic Acid