Fgf-2 overexpression increases excitability and seizure susceptibility but decreases seizure-induced cell loss.
Fibroblast growth factor 2 (FGF-2) has multiple, pleiotropic effects on the nervous system that include neurogenesis, neuroprotection and neuroplasticity. Thus, alteration in FGF-2 expression patterns may have a profound impact in brain function, both in normal physiology and in pathology. Here, we used FGF-2 transgenic mice (TgFGF2) to study the effects of endogenous FGF-2 overexpression on susceptibility to seizures and to the pathological consequences of seizures. TgFGF2 mice display increased FGF-2 expression in hippocampal pyramidal neurons and dentate granule cells. Increased density of glutamatergic synaptic vesicles was observed in the hippocampus of TgFGF2 mice, and electrophysiological data (input/output curves and patch-clamp recordings in CA1) confirmed an increase in excitatory inputs in CA1, suggesting the presence of a latent hyperexcitability. Indeed, TgFGF2 mice displayed increased susceptibility to kainate-induced seizures compared with wild-type (WT) littermates, in that latency to generalized seizure onset was reduced, whereas behavioral seizure scores and lethality were increased. Finally, WT and TgFGF2 mice with similar seizure scores were used for examining seizure-induced cellular consequences. Neurogenesis and mossy fiber sprouting were not significantly different between the two groups. In contrast, cell damage (assessed with Fluoro-Jade B, silver impregnation and anti-caspase 3 immunohistochemistry) was significantly lower in TgFGF2 mice, especially in the areas of overexpression (CA1 and CA3), indicating reduction of seizure-induced necrosis and apoptosis. These data suggest that FGF-2 may be implicated in seizure susceptibility and in seizure-induced plasticity, exerting different, and apparently contrasting effects: favoring ictogenesis but reducing seizure-induced cell death.
Zucchini
Silvia
S
Section of Pharmacology, Department of Clinical Experimental Medicine, Section of Pathology, National Institute of Neuroscience and Neuroscience Center, University of Ferrara, 44100 Ferrara, Italy.
Buzzi
Andrea
A
Barbieri
Mario
M
Rodi
Donata
D
Paradiso
Beatrice
B
Binaschi
Anna
A
Coffin
J Douglas
JD
Marzola
Andrea
A
Cifelli
Pierangelo
P
Belluzzi
Ottorino
O
Simonato
Michele
M
D000818:Animals; D016923:Cell Death / Q000235:genetics; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000235:genetics*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D013572:Synaptic Vesicles / Q000378:metabolism / Q000648:ultrastructure
D003292:Convulsants; D016222:Fibroblast Growth Factor 2; D018698:Glutamic Acid