DEVELOPMENT OF LONG-DISTANCE EFFERENT PROJECTIONS FROM FETAL HIPPOCAMPAL GRAFTS DEPENDS UPON PATHWAY SPECIFICITY AND GRAFT LOCATION IN KAINATE-LESIONED ADULT HIPPOCAMPUS

Fetal hippocampal cells grafted into the excitotoxically lesioned hipp ocampus of adult rats are capable of extending axonal projections into the host brain. We hypothesize that the axonal growth of grafted feta l cells into specific host targets, and the establishment of robust lo ng-distance efferent graft projections, require placement of fetal cel ls in close proximity to appropriate axon guidance pathways. Intracere broventricular administration of kainic acid in adult rats leads to a specific loss of hippocampal CA3 pyramidal neurons. We grafted 5'-brom odeoxyuridine-labeled embryonic day 19 hippocampal cells into adult hi ppocampus at four days post-kainic acid lesion, and quantitatively mea sured the projection of grafted cells into the contralateral hippocamp us and the septum after three to four months survival using Fluoro-Gol d and -dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine (DiI) tracing . Grafts located in or near the degenerated CA3 cell layer exhibited n umerous neurons which established commissural projections with the con tralateral hippocampus. However, such projections did not occur in int rahippocampal grafts located away from the CA3 cell layer. In contrast , neurons in all grafts established robust projections into the septum regardless of location within hippocampus although grafts located nea r the degenerated CA3 cell layer displayed more neurons with such proj ections. Location of grafted cells clearly influences the development of efferent graft projections into distant targets in the adult host b rain, particularly access to axon guidance pathways to facilitate the formation of projections. The establishment of robust long-distance co mmissural projections of fetal hippocampal grafts is clearly dependent on their placement in or near the degenerated CA3 cell layer, suggest ing that appropriate axon guidance pathways for commissural pathways a re tightly focussed near this cell layer. However, the establishment o f septal projections of these grafts was not dependent on specific loc ation within the CA3 cell layer, suggesting that axonal guidance mecha nisms to the septum are more diffuse and not limited to the CA3 dendri tic layers. The results underscore that Fetal hippocampal grafts are c apable of partly restoring lesioned hippocampal circuitry in adult ani mals when appropriately placed in the host hippocampus. Copyright (C) 1996 IBRO. Published by Elsevier Science Ltd.