Enhanced graft survival in the hippocampus following selective denervation

Abstract

The trophic effects of denervation on the survival of fetal cholinergic neuronal cell suspensions grafted to the hippocampal formation of the rat were assessed in the present study. Young adult female rats were injected with cell suspensions of neurons obtained from the fetal basal forebrain region into the hippocampal formation simultaneously with (or without) a fimbria-fornix transection, which removes the hippocampal cholinergic afferents. Four to six months later, one group of grafted animals was evaluated histochemically for: transplant volume; number of acetylcholinesterase-positive cells, and size of acetylcholinesterase-positive cells in the graft. A parallel study was conducted to determine the total number and size of the acetylcholinesterase-positive cells in the septal-diagonal band-substantia innominata complex of the adult rat, to match with the cell survival and growth in the grafts. A second group of grafted rats was taken in parallel for biochemical analysis of choline acetyltransferase activity in the grafted hippocampus. The transplant volume in the rats with fimbria-fornix transection was greater than twice the volume seen in animals without fimbria-fornix lesion. In addition, the number of acetylcholinesterase-positive cells in the transplant was twice as great in the denervated animals as in the non-denervated ones. However, the number of acetylcholinesterase-positive cells per mm3 of graft volume did not differ between the two groups, suggesting that the trophic effect of the denervation was not specific for the cholinergic neurons, but affected the entire grafted tissue. The hippocampal choline acetyltransferase activity of the animals that received the fimbria-fornix lesion simultaneously with transplantation was about three times higher than that of the rats that received grafts but no simultaneous fimbria-fornix transection. A control experiment with animals that received an aspirative lesion of the retrosplenial cortex, transecting the perforant path input, revealed no enhancing effect of hippocampal choline acetyltransferase activity over non-lesioned grafted animals. Thus, the denervation-enhancing effects of the fimbria-fornix lesion appear to be selective and not the result of a general wound-induced mechanism. These results strongly support the contention that neurotrophic factors are released as a result of denervation in the adult hippocampal formation, and that these neurotrophic factors can support survival and growth of central cholinergic neurons. However, the factors involved do not appear to be specific for the cholinergic neurons, but rather have their trophic effects on many types of cells.