Abstracts

RATIONALE: Previous studies have reported that intrahippocampal injection of kainic acid in adult mice results, after a latent period of 15 days, in recurrent hippocampal epileptic discharges associated with cell loss in CA1 and hilus and dispersion of dentate gyrus granular neurons. In this model of Mesial Temporal Lobe Epilepsy (MTLE), a lasting overexpression of BDNF mRNA has been observed in dispersed granule cells. According to previous reports, this increase of BDNF could trigger epileptogenesis. However, other data suggest that the overexpression of BDNF may constitute an endogenous regulatory mechanism able to restrain hippocampal epileptogenesis. The aim of our study was to clarify the consequences of BDNF overexpression on hippocampal epileptogenesis in the kainate mouse model. Therefore, in the present study, we determined (i) the time-course of hippocampal expression of BDNF during epileptogenesis, (ii) the consequences of a blockade of BDNF expression and (iii) the consequences of an infusion of recombinant BDNF on epileptogenesis and granule cell dispersion.
METHODS: Adult C57/Bl6 mice were stereotaxically injected with 1 nmol of kainate (50nL) in the right dorsal hippocampus and implanted with a bipolar electrode at the injection site. Hippocampal BDNF protein levels were measured with an Enzyme Linked Immunosorbent Assay (ELISA). Chronic intrahippocampal infusions of BDNF antisense oligodeoxynucleotides (ODN) (0.5 nmol/h) or recombinant BDNF (0.85[mu]g/h) were performed during 7 days with mini-osmotic pumps.
RESULTS: BDNF protein levels were significantly increased in the injected hippocampus during the first 3 weeks after kainate injection with a maximum at 16 days, as compared to contralateral side. During this period, dentate gyrus thickness rapidly increased and recurrent epileptic discharges progressively developed in the injected hippocampus. A 7 day infusion of BDNF antisense ODN in kainate treated mice prevented the dispersion of granule cells, but not the cell loses, and only continuous spiking activity was observed, as compared to animals infused with mismatch ODN. When kainate-treated mice were infused with human recombinant BDNF, a similar pattern of hippocampal sclerosis and epileptic discharges was observed, as in kainate and PBS treated mice.
CONCLUSIONS: Our data confirm the key role of BDNF overexpression in the enlargement of granule cells. Moreover, these results support the hypothesis that BDNF overexpression and granule cell dispersion could participate in the organization of the hippocampal kainate-induced hyperactivity into recurrent epileptic discharges.
[Supported by: INSERM]