Temporal Profile of Clinical Signs and Histopathologic Changes in an F-344 Rat Model of Kainic Acid–induced Mesial Temporal Lobe Epilepsy

Abstract

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; amygdaloid 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.

Neurogenesis in a Young Dog With Epileptic Seizures

“…5 In rodent models of this condition, abnormal hippocampal neurogenesis has been found in adult animals, and these new-born neurons are predominantly in ectopic hilar regions but also in the dentate granule cell layer. 8,10,13,14 Similar observations have been reported in children. 3 It is now widely accepted that neurogenesis occurs under physiological conditions in adult mammals, especially in the dentate gyrus of the hippocampus and the subventricular zone of lateral ventricles.…”

Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain

“…The mechanisms by which rapamycin produces these positive effects, however, are unclear. For the present study, we examined several hippocampal abnormalities implicated in the development of temporal lobe epilepsy (Parent and Kron, 2012; Hester and Danzer, 2014), including mossy fiber sprouting (Buckmaster, 2014), hilar ectopic granule cell accumulation (Scharfman and Pierce, 2012), basal dendrite formation (Ribak et al, 2012), reactive astrogliosis and microgliosis (Sharma et al, 2008; Gibbons et al, 2013) and mossy cell loss (Jinde et al, 2013). Consistent with previous studies (Zeng et al, 2009; Buckmaster et al, 2009), we observed a significant reduction in mossy fiber sprouting with rapamycin treatment.…”

Kainic Acid-induced F-344 Rat model of Mesial Temporal Lobe Epilepsy: Gene Expression and Canonical Pathways

“…On days 14 and 28, hippocampi were collected for gene array from only those rats that developed spontaneous motor seizures. In the companion study (Sharma et al 2008), histopathological changes relevant to the categories of neuronal degeneration, aberrant mossy fiber sprouting, microgliosis, and astrogliosis were recorded at days 3, 6, 14, and 28. Severity scores for each of the categories at each time point were generated and are shown in Figure 1.…”

“…To obtain a better understanding of the underlying molecular mechanisms and identify potential biomarkers of lesion progression, we used a rat kainic acid (KA) treatment model of MTLE coupled with global gene expression analysis to examine temporal (four hours, days 3, 14, or 28) gene regulation relative to hippocampal histopathological changes. The authors recommend reviewing the companion histopathology paper (Sharma et al 2008) to get a better understanding of the work presented here. Analysis of filtered gene expression data using Ingenuity Pathways Analysis (Ingenuity Systems, http://www.ingenuity.com) revealed that a number of genes pertaining to neuronal plasticity (RhoA, Rac1, Cdc42, BDNF, and Trk), neurodegeneration (Caspase3, Calpain 1, Bax, a Cytochrome c, and Smac/Diablo), and inflammation/immune-response pathways (TNF-a, CCL2, Cox2) were modulated in a temporal fashion after KA treatment.…”