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

Abstract

Purpose: 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 here 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 in the rat hippocampus 3 days after an epileptogenic insult (pilocarpine-induced status epilepticus). Continuous video-EEG monitoring was initiated 7 days after status epilepticus, and animals were sacrificed at 28 days for analysis of cell loss (that was measured using NeuN immunofluorescence) and mossy fiber sprouting (measured using dynorphin A immunohistochemistry). Key Findings: The vector expressing FGF-2 and BDNF decreased in parallel mossy fiber sprouting and the frequency and severity of spontaneous seizures. The effect on sprouting strictly correlated with the cell loss in the terminal fields of physiological mossy fiber innervation (mossy cells in the dentate gyrus hilus and CA3 pyramidal neurons). Significance: 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, i.e. reducing some forms of circuit reorganization