The structure of cerebral cortex in the rat following prenatal administration of 6-hydroxydopamine

Abstract

The early, prenatal formation of noradrenergic projections to the forebrain has led to the proposition that these axons exert a trophic influence on cerebral cortex during ontogeny. To test this hypothesis, we have examined a number of different structural features of cortical development following prenatal lesions of the ascending noradrenergic axons. The parameters that were analyzed include cytoarchitecture, dendritic morphology, and the distribution of monoaminergic and nonmonoaminergic cortical afferents. Rat fetuses were administered the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) by transuterine, intraperitoneal injection on embryonic day 17. Vehicle-injected controls and fetuses treated with the catecholamine uptake inhibitor desmethylimipramine (DMI) prior to 6-OHDA were prepared. After reaching maturity (200-300 g), the brain of treated and control rats were examined using Nissl and Golgi preparations (for cytoarchitecture and dendritic morphology), histofluorescence (for monoaminergic afferents, especially dopaminergic axons), and serotonin and dopamine-beta-hydroxylase (DBH) immunocytochemistry. Effective lesioning of the ascending noradrenergic system was confirmed in each case, using DBH immunocytochemistry. Prenatal treatment with 6-OHDA resulted in complete and long-lasting destruction of the noradrenergic innervation of the cerebral cortex, along with hyperinnervation of the diencephalon and brain stem. Despite the widespread denervation of cerebral cortex, no significant alterations in cytoarchitecture, dendritic morphology, or spine counts were found in treated brains. In particular, no abnormalities were observed in the apical dendrites of layer VI pyramidal cells, based on qualitative criteria. The distribution, density and morphology of serotonergic and dopaminergic afferents were unaffected. Thalamocortical afferents had developed normally as reflected by the cortical barrels. In 33% of the 6-OHDA-treated fetuses foci of ectopic neurons were found at the cortical surface. The ectopias contain neuronal processes, somata, and synapses interspersed with collagen and other connective tissue elements. While the ectopias may result from selective damage to the noradrenergic neurons, the finding of similar (but smaller) malformations in DMI-protected animals is equally consistent with a non-specific effect of 6-OHDA upon non-adrenergic cells. The examination of intervening stages will be needed to resolve this question. Based on the parameters of cortical structure analyzed in this study we conclude that the neocortex develops normally even in the absence of the noradrenergic system.