CONTRASTING EFFECTS OF FETAL CA1 AND CA3 HIPPOCAMPAL GRAFTS ON DEFICITS IN SPATIAL-LEARNING AND WORKING-MEMORY INDUCED BY GLOBAL CEREBRAL-ISCHEMIA IN RATS

Functional effects of fetal hippocampal field grafts were assessed in rats with spatial learning and memory impairments following global cer ebral ischaemia. Experiment 1 examined effects of grafts dissected fro m fields CA1 and CA3 at embryonic day 19 and from the dentate gyrus at postnatal day 1. Cell suspensions (15,000 cells/site) were implanted bilaterally at two points above the dorsal CA1 area two weeks after fo ur-vessel occlusion (electrocoagulation of the vertebral arteries foll owed 24 h later by occlusion of the carotid arteries for 15 min). Hist ological examination showed that CA1 neuronal loss (60-70%) was equiva lent in all ischaemic groups and that 80% of CA1 and 60% of CA3 grafts survived and were sited appropriately in the alveus or corpus callosu m above the area of ischaemic CA1 damage in the host, but there was no survival of dentate grafts. Results from rats with poor pyramidal cel l graft survival were excluded, but those from rats with non-surviving dentate grafts were retained as an additional control group. Acquisit ion in the water maze was examined nine and 25 weeks after transplanta tion, and spatial working memory was assessed in three-door runway and water maze matching-to-position tasks 19 and 28 weeks after grafting, respectively. For water maze acquisition rats were trained with two t rials/day and a 10 min inter-trial interval for 10-12 days to locate a submerged platform. Ischaemic rats with CA1 grafts learned the platfo rm position as rapidly as non-ischaemic controls, searched appropriate ly in the training quadrant and were accurate in heading towards the p latform, but were initially impaired on recall of the precise platform position on probe trials with the platform removed. Performance of is chaemic controls and groups with CA3 and non-surviving dentate graft g roups was significantly impaired relative to controls and to the CA1 g rafted group. The CA1 grafted group was also as successful as controls in matching-to-position in the water maze and substantially superior to the other ischaemic groups, assessed using three trials/day, with a 30-s inter-trial interval and a different platform position on each d ay. In a more complex matching-to-position task in the three-door runw ay, the performance of the CA1 grafted group was significantly impaire d relative to controls, although superior to that of the other ischaem ic control and graft groups. Functional recovery with CA1, but not CA3 , grafts in ischaemic rats was replicated in a second experiment which assessed water maze acquisition and working memory at 10 and 14 weeks after transplantation, in rats with 90% graft survival. These results indicate that long-lasting, task-dependent improvements can be seen i n ischaemic rats with CA1 fetal grafts in both aversively and appetiti vely motivated spatial learning tasks. The findings suggest that funct ional recovery requires homotypic replacement of CA1 cells damaged by ischaemia, rather than provision of structurally similar glutamate-rel easing CA3 pyramidal cells.