Localized overexpression of FGF-2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpine-induced status epilepticus.
OBJECTIVE
We have recently reported that viral vector-mediated supplementation of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) in a lesioned, epileptogenic rat hippocampus limits neuronal damage, favors neurogenesis, and reduces spontaneous recurrent seizures. To test if this treatment can also prevent hippocampal circuit reorganization, we examined here its effect on mossy fiber sprouting, the best studied form of axonal plasticity in epilepsy.


METHODS
A herpes-based vector expressing FGF-2 and BDNF was injected into the rat hippocampus 3 days after an epileptogenic insult (pilocarpine-induced status epilepticus). Continuous video-electroencephalography (EEG) monitoring was initiated 7 days after status epilepticus, and animals were sacrificed at 28 days for analysis of cell loss (measured using NeuN immunofluorescence) and mossy fiber sprouting (measured using dynorphin A immunohistochemistry).


RESULTS
The vector expressing FGF-2 and BDNF decreased both mossy fiber sprouting and the frequency and severity of spontaneous seizures. The effect on sprouting correlated strictly with the cell loss in the terminal fields of physiologic mossy fiber innervation (mossy cells in the dentate gyrus hilus and CA3 pyramidal neurons).


CONCLUSIONS
These data suggest that the supplementation of FGF-2 and BDNF in an epileptogenic hippocampus may prevent epileptogenesis by decreasing neuronal loss and mossy fiber sprouting, that is, reducing some forms of circuit reorganization.
Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Beatrice
B
Paradiso
Silvia
S
Zucchini
Tao
T
Su
Roberta
R
Bovolenta
Elena
E
Berto
Peggy
P
Marconi
Andrea
A
Marzola
Graciela
G
Navarro Mora
Paolo F
PF
Fabene
Michele
M
Simonato
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003587:Cytomegalovirus; D004399:Dynorphins / Q000235:genetics; D004569:Electroencephalography; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics*; D005822:Genetic Vectors; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000473:pathology*; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics*; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012815:Signal Processing, Computer-Assisted; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*; D014741:Video Recording
D019208:Brain-Derived Neurotrophic Factor; D016222:Fibroblast Growth Factor 2; D004399:Dynorphins