Retrograde degenerative changes in the substantia nigra pars compacta following an excitotoxic lesion of the striatum

Abstract

The retrograde changes induced by an excitotoxic lesion of the striatum (Str) on the neurons in substantia nigra pars compacta (SNc) projecting to the neuron-depleted region were investigated in adult rats. The retrograde tracer Fluoro-Gold (FG) was injected bilaterally into the Str. 2 weeks later, the excitotoxic amino acid ibotenic acid (IA) was injected unilaterally into the same structure. At four different time points after the lesion (1 week and 1,2 and 3 months, respectively), the size of the FG-labelled cells and number of tyrosine hydroxylase (TH)-positive cells in the SNc were evaluated on the lesioned and control sides. Parallel groups of animals received suspension grafts of fetal striatal tissue into the lesioned striata. At 1 week and 1 month after lesion, there were no changes in cell size, number of TH-positive cells or number of FG-labelled cells expressing TH in the SNc. At 2 and 3 months, however, there was a significant 30% shrinkage of the FG-labelled SNc cells but no evident decrease in TH-positive cell number, or in the expression of the TH protein, on the lesioned side as compared with the non-lesioned control side. Striatal transplants placed into the lesioned Str did not counteract this effect. This finding that an axon-sparing lesion of target cells results in cell shrinkage but no cell loss of the neurons that project to the lesioned area is in line with that has been shown to occur after similar lesions in the cholinergic septohippocampal and basalo-cortical systems. These slowly developing atrophic changes, without cell loss, induced in the nigral dopamine neurons by removal of the striatal target neurons should provide a useful model for the in vivo evaluation of the effect of putative target-derived neurotrophic factors in the nigrostriatal dopamine system.