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Temporal Profile of Clinical Signs and Histopathologic Changes in an F-344 Rat Model of Kainic Acid–induced Mesial Temporal Lobe Epilepsy
1 Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA Correspondence: Address correspondence to: Alok K. Sharma, Department of Pathology, Covance Laboratories, Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2523, USA; e-mail:Alok.Sharma{at}covance.com. Since there is limited information in the literature, the purpose of this study was to investigate clinical signs, morphology, and temporal progression of lesions from Days 3 to 168 in a kainic acid (KA)-induced Fischer-344 (F-344) rat model of mesial temporal lobe epilepsy (MTLE). Following a single KA subcutaneous dose of 9 mg/kg to young adult male rats, 95% survived, 93% exhibited status epilepticus, and 80% eventually developed spontaneous motor seizures. Histopathology included hematoxylin and eosin (H&E), autofluorescence, Fluoro-Jade B, Timm’s, ED-1/CD68, GFAP, doublecortin, and Ki-67. Neuronal degeneration occurred on Day 3 in the hippocampal CA1, CA3, and dentate hilar regions; amyg-daloid and thalamic nuclei; and frontoparietotemporal, entorhinal and piriform cortices. Degeneration severity peaked on Day 6 and decreased progressively until Day 168. Aberrant mossy fiber (MF) sprouting was present in the inner molecular layer of dentate gyrus on Days 6–168. Microliosis and astrogliosis peaked on Day 28 and generally colocalized with the distribution of neuronal degeneration. Important correlates to human MTLE included induction of spontaneous seizures, more severe neuronal damage of CA1 than CA3 (in contrast to other animal models but similar to humans), hilar neuronal loss, activated microgliosis and astrogliosis, aberrant MF sprouting, and dentate granule cell neurogenesis. Aberrant MF sprouting prior to spontaneous motor seizures and reduced seizure frequency with a decrease in aberrant MF sprouting support the hypothesis that MF sprouts are necessary for spontaneous seizure generation and maintenance.
Key Words: mesial temporal lobe epilepsy (MTLE) • Fischer-344 rat • animal model • histopathology; lesions • neurodegeneration • microgliosis • astrogliosis • mossy fiber sprouting; neurogenesis Abbreviations: BrdU, bromodeoxyuridine (5-bromo-2-deoxyuridine) • CA, cornu ammonis • DCX, doublecortin • DG, dentate gyrus • EC, entorhinal cortex • EPSC, excitatory postsynaptic current • F-344, Fischer 344 • FJB, fluoro-jade B • FPT, frontoparietotemporal • HS, hippocampal sclerosis • i.p., intraperitoneal • i.v., intravenous • GABA, gamma-aminobutyric acid • KA, kainic acid • MF, mossy fiber • MTLE, mesial temporal lobe epilepsy • s.c., subcutaneous • SD, Sprague-Dawley • SGZ, subgranular zone • TLE, temporal lobe epilepsy
Toxicologic Pathology, Vol. 36, No. 7,
932-943 (2008) This article has been cited by other articles:
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