title: Repeated low-dose kainate administration in C57BL/6J mice produces temporal lobe epilepsy pathology but infrequent spontaneous seizures.
abstract: More efficient or translationally relevant approaches are needed to model acquired temporal lobe epilepsy (TLE) in genetically tractable mice. The high costs associated with breeding and maintaining transgenic, knock-in, or knock-out lines place a high value on the efficiency of induction and animal survivability. Herein, we describe our approaches to model acquired epilepsy in C57BL/6J mice using repeated, low-dose kainate (KA) administration paradigms. Four paradigms (i.p.) were tested for their ability to induce status epilepticus (SE), temporal lobe pathology, and the development of epilepsy. All four paradigms reliably induce behavioral and/or electrographic SE without mortality over a 7d period. Two of the four paradigms investigated produce features indicative of TLE pathology, including hippocampal cell death, widespread astrogliosis, and astrocyte expression of mGluR5, a feature commonly reported in TLE models. Three of the investigated paradigms were able to produce aberrant electrographic features, such as interictal spiking in cortex. However, only one paradigm, previously published by others, produces spontaneous recurrent seizures over an eight week period. Presentation of spontaneous seizures is rare (N=2/14), with epilepsy preferentially developing in animals having a high number of seizures during SE. Overall, repeated, low-dose KA administration improves the efficiency and pathological relevance of a systemic KA insult, but does not produce a robust epilepsy phenotype under the experimental paradigms described herein.
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, 401 MREB, 20N. 1900E, Salt Lake City, UT 84132, United States. Electronic address: Anthony.Umpierre@utah.edu.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Umpierre
authors.affiliation: Dept. of Pharmacology & Toxicology, University of Utah, College of Pharmacy, 30N. 1900E, Salt Lake City, UT 84112, United States. Electronic address: isaiahvbennett98@gmail.com.
authors.forename: Isaiah V
authors.initials: IV
authors.lastname: Bennett
authors.affiliation: Dept. of Pharmacology & Toxicology, University of Utah, College of Pharmacy, 30N. 1900E, Salt Lake City, UT 84112, United States. Electronic address: U0879974@utah.edu.
authors.forename: Lismore D
authors.initials: LD
authors.lastname: Nebeker
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, United States; Dept. of Bioengineering, University of Utah, 36S. Wasatch Drive, Rm. 3100, Salt Lake City, UT 84112, United States. Electronic address: Thomas.Newell@utah.edu.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Newell
authors.affiliation: Dept. of Pharmacology & Toxicology, University of Utah, College of Pharmacy, 30N. 1900E, Salt Lake City, UT 84112, United States. Electronic address: U0667419@utah.edu.
authors.forename: Bruce B
authors.initials: BB
authors.lastname: Tian
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, United States; Dept. of Bioengineering, University of Utah, 36S. Wasatch Drive, Rm. 3100, Salt Lake City, UT 84112, United States. Electronic address: K.Thomson@utah.edu.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Thomson
authors.affiliation: Dept. of Pharmacology & Toxicology, University of Utah, College of Pharmacy, 30N. 1900E, Salt Lake City, UT 84112, United States; Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, United States; Department of Pharmacy, University of Washington, Box 357630, H375 Health Science Building, Seattle, WA 98195, United States. Electronic address: hswhite@uw.edu.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.affiliation: Dept. of Biomedical Engineering, Boston University, 44 Cummington Mall, Rm. 403, Boston, MA 02215, United States. Electronic address: jwhite@bu.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: White
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, 401 MREB, 20N. 1900E, Salt Lake City, UT 84132, United States; Dept. of Pharmacology & Toxicology, University of Utah, College of Pharmacy, 30N. 1900E, Salt Lake City, UT 84112, United States; Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, United States. Electronic address: Karen.Wilcox@hsc.utah.edu.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wilcox
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000473:pathology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064529:Receptor, Metabotropic Glutamate 5 / Q000096:biosynthesis; D012640:Seizures / Q000139:chemically induced; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology
chemical_list: D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D007608:Kainic Acid
keywords: Astrogliosis; C57 (C57BL/6J); Cell death; Kainate; Neurodegeneration; Seizure; Temporal lobe epilepsy; Valproic acid; mGluR5