FGF-2 Overexpression Increases Excitability and Seizure Susceptibility but Decreases Seizure-Induced Cell Loss

Abstract

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.

Localized delivery of fibroblast growth factor–2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model

“…The volume of the dorsal hippocampus was calculated using a stereological approach based on the principle of Cavalieri (36). The degree of cell damage was quantified using two approaches: the ''neurodegeneration score'' (37) and a thresholding of digital images (38). Counting of cells positive for the different markers was conducted on one of every 26 sections across the entire dorsal hippocampus (i.e., nine regularly spaced sections per animal).…”

Enhancement of GABA A -current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy

“…The quantification method was based on thresholding of digital images and calculation of the mean percent of FJC-positive pixels in the sections. Statistical analysis was conducted using the Mann-Whitney two-tailed u test (38). See SI Materials and Methods for further information.…”

Transient Protective Effect of B-Vitamins in Experimental Epilepsy in the Mouse Brain

“…The hippocampal area was subjected to histochemical investigations using a TUNEL assay. According to Wang et al (2008) and Zucchini et al (2008), TUNEL-positive cells were counted in corresponding hippocampal CA3 areas 3 days following kainate application (Figs. 4 and 5).…”