ENHANCED CELL-SURVIVAL IN FETAL HIPPOCAMPAL SUSPENSION TRANSPLANTS GRAFTED TO ADULT-RAT HIPPOCAMPUS FOLLOWING KAINATE LESIONS - A 3-DIMENSIONAL GRAFT RECONSTRUCTION STUDY

The success of fetal neural transplantation in alleviating neurologica l dysfunction depends significantly on the degree of graft cellular su rvival and dispersion within the host. We hypothesize that various les ion-induced host factors, such as trophic support and denervation, enh ance these graft factors differentially following unilateral intracere broventricular kainic acid lesions. We have performed quantitative gra ft reconstructions of embryonic day 19 fetal hippocampal cells transpl anted at different post-lesion delays (four, 11, 26 and 60 days) into adult hippocampus. We have used a permanent graft prelabel (5'-bromode oxyuridine) which allows unambiguous identification of graft cell loca tion in the host. Cellular integration of grafted cells was rigorously assessed by calculating both absolute cell survival (cells recovered/ cells injected) and quantitative cell dispersion from the graft inject ion site. Graft cell survival and graft volume were dramatically enhan ced in transplants performed ipsilateral to the kainic acid lesion, to a maximum of 77% cell recovery at a post-lesion graft delay of four d ays. Cell survival decreased over time after the lesion to the level o f the contralateral grafts by 60 days post-lesion (33% cell survival), though cell survival on either side remained significantly greater th an grafts into normal hosts (18% survival). The time-course of post-le sion enhanced survival (four to 26 days) in hippocampus ipsilateral to the lesion strongly correlated with reported peak neurotrophic activi ty (four to 30 days). Graft cell dispersion was limited in this model, averaging less than 500-mu m-cell movement; there were no differences compared to transplants grafted into normal hippocampus. Timm's stain ing demonstrated host mossy fiber innervation of transplants to be den ser ipsilateral to the kainic acid lesion, resulting in a partial decr ease in dentate supragranular sprouting near appropriate grafts placed at early post-lesion time points. These results suggest that lesion-i nduced trophic support and denervation lead to improved graft cell sur vival but not graft cell dispersion. The improved survival of grafts t ransplanted into hippocampus contralateral to the lesion, compared to transplants in normal hippocampus, suggests that denervation alone exe rts a significant effect on graft cell survival. However, this denerva tion effect on graft cell survival is significantly less than the comb ination of both enhanced neurotrophic factors and denervation observed ipsilateral to the lesion.