Abstracts

RATIONALE: Intracerebroventricular kainic acid (ICV KA) administration in rat, a model of temporal lobe epilepsy, causes degeneration of hippocampal CA3 pyramidal neurons and dentate hilar cells, the target cells of dentate granule cell axons (mossy fibers). This leads to a robust but aberrant sprouting of mossy fibers into the deafferented dentate supragranular layer. As this sprouting is linked to an increased seizure susceptibility of the dentate gyrus, strategies that restrain mossy fiber sprouting into the dentate supragranular layer are of considerable significance. We hypothesize that grafting of specific fetal hippocampal cells into the CA3-lesioned adult hippocampus results in the formation of appropriate connectivity between grafted cells and the host dentate gyrus, which in turn leads to a durable suppression of aberrant mossy fiber sprouting into the dentate supragranular layer.
METHODS: Embryonic day 19 hippocampal CA3 or CA1 cells were grafted into the CA3 region of the adult hippocampus at 4 or 45 days after the ICV KA administration, and the aberrant sprouting of mossy fibers into the dentate supragranular layer was quantified after 8-12 months of grafting using Timm[ssquote]s histochemical staining. For comparison, the extent of mossy fiber sprouting was also quantified from [dsquote]lesion-only[dsquote] animals at 4-12 months post-lesion. Graft axon growth into the deafferented sites of the lesioned hippocampus was analyzed using transplantation of fetal mouse hippocampal cells into the lesioned rat hippocampus and immunostaining for the mouse-specific antigen M6.
RESULTS: Fetal CA3 cell grafts placed close to the lesioned CA3 region received dense projections from the host mossy fiber bundle. Whereas, similarly placed CA1 cell grafts received no such projections. Further, in animals receiving CA3 cell grafts, the overall extent of aberrant mossy fiber sprouting was radically diminished, in comparison to the [dsquote]lesion-only[dsquote] animals. In contrast, in animals receiving CA1 cell grafts, the dentate supragranular layer mossy fiber sprouting was closer to [dsquote]lesion only[dsquote] animals. Analyses of graft axon growth revealed robust graft efferent projections into the dentate supragranular layer in animals receiving CA3 cell grafts but not in animals receiving CA1 cell grafts.
CONCLUSIONS: These results underscore that grafting of specific fetal hippocampal cells into the lesioned adult hippocampus can considerably inhibit the formation of aberrant circuitry by facilitating an appropriate restitution of the disrupted circuitry. These results have significance towards the development of cell transplantation therapy for temporal lobe epilepsy.
[Supported by: grants from the Department of Veterans Affairs (VA Merit Review Award to A.K.S.) and National Institutes of Health (NINDS R01 NS36741 to A.K.S.).]