Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy

Abstract

The links among the extent of hippocampal neurodegeneration, the frequency of spontaneous recurrent motor seizures (SRMS), and the degree of aberrant mossy fiber sprouting (MFS) in temporal lobe epilepsy (TLE) are a subject of contention because of variable findings in different animal models and human studies. To understand these issues further, we quantified these parameters at 3-5 months after graded injections of low doses of kainic acid (KA) in adult F344 rats. KA was administered every 1 hr for 4 hr, for a cumulative dose of 10.5 mg/kg bw, to induce continuous stages III-V motor seizures for >3 hr. At 4 days post-KA, the majority of rats (77%) exhibited moderate bilateral neurodegeneration in different regions of the hippocampus; however, 23% of rats exhibited massive neurodegeneration in all hippocampal regions. All KA-treated rats displayed robust SRMS at 3 months post-KA, and the severity of SRMS increased over time. Analyses of surviving neurons at 5 months post-KA revealed two subgroups of rats, one with moderate hippocampal injury (HI; 55% of rats) and another with widespread HI (45%). Rats with widespread HI exhibited greater loss of CA3 pyramidal neurons and robust aberrant MFS than rats with moderate HI. However, the frequency of SRMS (approximately 3/hr) was comparable between rats with moderate and widespread HI. Thus, in comparison with TLE model using Sprague-Dawley rats (Hellier et al. [1998] Epilepsy Res. 31:73-84), a much lower cumulative dose of KA leads to robust chronic epilepsy in F344 rats. Furthermore, the occurrence of SRMS in this model is always associated with considerable bilateral hippocampal neurodegeneration and aberrant MFS. However, more extensive hippocampal CA3 cell loss and aberrant MFS do not appear to increase the frequency of SRMS. Because most of the features are consistent with mesial TLE in humans, the F344 model appears ideal for testing the efficacy of potential treatment strategies for mesial TLE.

Strategies for promoting anti-seizure effects of hippocampal fetal cells grafted into the hippocampus of rats exhibiting chronic temporal lobe epilepsy

“…As majority of animals (>90%) exhibited >10 stages IV-V seizures during the 60 min after the 3rd KA injection, the 4th KA injection was reduced to 1.5 mg/kg b.w. Thus, each animal received a total KA dose of 10.5 mg/kg b.w., which is consistent with our recent study (Rao et al, 2006a). The motor seizures were characterized by unilateral forelimb clonus with lordotic posture (stage III seizures), bilateral forelimb clonus and rearing (stage IV seizures) and bilateral forelimb clonus with rearing and falling (stage V seizures).…”

“…Although the frequency of seizures reported for different animal models of epilepsy in published reports varies considerably, rats exhibiting 3.0-3.5 seizures/8-h duration can be classified as rats with significant chronic epilepsy. However, in the same KA model, we have encountered rats with highly robust chronic epilepsy (8.0-12 seizures/8-h duration; Rao et al, 2006a). As this study represents our initial assessment of the effects of HFC grafting on chronic seizures, we chose rats with significant chronic epilepsy (instead of rats with highly robust chronic epilepsy) for all groups.…”

The Developmental Stage of Dentate Granule Cells Dictates Their Contribution to Seizure-Induced Plasticity

“…Furthermore, dendrites present on ectopic cells were excluded, as they were already located in the hilus. Others have demonstrated that aberrantly developing adult-born neurons stably integrate into the dentate circuitry (Scharfman et al, 2000;McCloskey et al, 2006) and that altered neurogenesis after SE is long lasting, with ectopic cells forming for many months after seizure induction (Rao et al, 2006;Jessberger et al, 2007). Thus, the extent of SE-induced neurogenesis abnormalities is likely even more severe than is suggested by our RV labeling.…”

Plasticity of hippocampal stem/progenitor cells to enhance neurogenesis in response to kainate‐induced injury is lost by middle age

“…Behavioral changes suggestive of motor seizures, normally observed after intraperitoneal injections of KA in non-anesthetized rats (Rao et al ., 2006c), were not seen in any of the rats receiving ICV KA injections under anesthesia. This is consistent with earlier observations that ICV KA administration, particularly at the low dose used in this study, does not produce motor seizures but consistently leads to hippocampal neurodegeneration (Shetty & Turner, 1999a,b;Shetty et al ., 2003Shetty et al ., , 2004Shetty et al ., , 2005b.…”