Effects of fetal hippocampal field grafts on ischaemic-induced deficits in spatial navigation in the water maze

Abstract

Transitory global cerebral ischaemia induced in rats by four vessel occlusion for 15 min produced substantial loss of CA1 cells in dorsal hippocampus, and minimal damage in other intra- and extrahippocampal forebrain regions examined. Ischaemic rats showed long-lasting deficits in spatial navigation in the water-maze, consisting of impaired learning to locate a hidden platform in a novel pool, a substantial increase in time spent searching close to the platform without finding it, and moderate deficits in matching to position in a working memory task. Groups of ischaemic rats were implanted with fetal tissue dissected from hippocampal CA1 field, containing glutamatergic CA1 pyramidal cells, from dentate gyrus, containing glutamatergic dentate granule cells, and from basal forebrain, containing cholinergic cells, with grafts sited in the alveus above the damaged CA1 region, for comparison with non-grafted ischaemic and non-ischaemic control groups, over a series of tests from four to 20 weeks after grafting. All ischaemic groups showed comparable acquisition deficits prior to transplantation, and similar loss of CA1 cells on post mortem examination. When tested in a familiar pool in retention and reversal learning of the original platform position, and a working memory task, all ischaemic rats performed better than in initial acquisition. However, rats receiving CA1 grafts showed the most consistent improvement relative to ischaemic controls. When tested in a second (i.e. novel) pool, ischaemic rats again showed marked impairment, whereas rats with CA1 grafts were significantly superior, and learned as rapidly as non-ischaemic controls. The performance of groups with dentate granule and basal forebrain grafts was similar to that of the non-grafted ischaemic control group throughout testing. These results suggest that ischaemic rats are impaired in the adaptive use of spatial information, as shown by acquisition and working memory deficits, but not in long- or short-term memory storage processes, and are also impaired in precise spatial localization. The effects of CA1 grafts in restoring spatial abilities, shown most clearly when rats were tested in a novel environment, suggest that these grafts may have assisted with repair to the damaged host circuit, rather than acted through the release of an appropriate neurotransmitter, since the glutamatergic dentate granule grafts were ineffective. However, CA1 grafts showed better survival and growth than the other types of transplant, so that functional recovery may have been related to graft viability rather than to the specific type of graft.