FETAL HIPPOCAMPAL CELLS GRAFTED TO KAINATE-LESIONED CA3 REGION OF ADULT HIPPOCAMPUS SUPPRESS ABERRANT SUPRAGRANULAR SPROUTING OF HOST MOSSYFIBERS

Selective lesion of the rat hippocampus using an intracerebroventricul ar administration of kainic acid (KA) represents an animal model for s tudying both lesion recovery and temporal lobe epilepsy This KA lesion leads initially to loss of CA3 hippocampal neurons, the postsynaptic target of messy fibers, and later results in aberrant messy fiber spro uting into the dentate supragranular layer (DSGL). Because of the clos e association of this aberrant messy fiber sprouting with an increase in the seizure susceptibility of the dentate gyrus, delayed therapeuti c strategies capable of suppressing the sprouting of messy fibers into the DSGL are of significant importance. We hypothesize that neural gr afting can restore the disrupted hippocampal messy fiber circuitry in this model through the establishment of appropriate messy fiber projec tions onto grafted pyramidal neurons and that these appropriate projec tions will lead to reduced inappropriate sprouting into the DSGL. Larg e grafts of Embryonic Day 19 hippocampal cells were transplanted into adult hippocampus at 4 days post-KA lesion. Aberrant messy fiber sprou ting was quantified after 3-4 months survival using three different me asures of Timm's staining density. Grafts located near the degenerated CA3 cell layer showed dense ingrowth of host messy fibers compared to grafts elsewhere in the hippocampus. Aberrant messy fiber sprouting t hroughout the dentate gyrus was dramatically and specifically reduced in animals with grafts near the degenerated CA3 cell layer compared to ''lesion only'' animals and those with ectopic grafts away from the C A3 region. These results reveal the capability of appropriately placed fetal hippocampal grafts to restore disrupted hippocampal messy fiber circuitry by attracting sufficient host messy fibers to suppress the development of aberrant circuitry in hippocampus. Thus, providing an a ppropriate postsynaptic target at early postlesion periods significant ly facilitates lesion recovery. The graft-induced long-term suppressio n of aberrant sprouting shown here may provide a new avenue for amelio ration of hyperexcitability that occurs following hippocampal lesions. (C) 1997 Academic Press.