Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy.
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.
Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, North Carolina 27710, USA.
Muddanna S
MS
Rao
Bharathi
B
Hattiangady
Doodipala S
DS
Reddy
Ashok K
AK
Shetty
D000818:Animals; D001522:Behavior, Animal; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D005452:Fluoresceins; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D007839:Functional Laterality / Q000502:physiology; D006624:Hippocampus / Q000473:pathology*; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000503:physiopathology*; D009478:Neuropeptide Y / Q000378:metabolism; D009930:Organic Chemicals; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012640:Seizures / Q000503:physiopathology*; D016622:Silver Staining / Q000379:methods; D013997:Time Factors
D005452:Fluoresceins; D009478:Neuropeptide Y; D009930:Organic Chemicals; C435731:fluoro jade; D010751:Phosphopyruvate Hydratase; D007608:Kainic Acid