Intrastriatal grafts derived from fetal striatal primordia: II. Reconstitution of cholinergic and dopaminergic systems

Abstract

Reconstitution of striatal cholinergic and dopaminergic systems was studied in intrastriatal grafts derived from embryonic day 15 rat striatal primordia and implanted into adult host rats in which unilateral ibotenic acid lesions had previously been made in the striatum. Histochemical, immunohistochemical, and ligand binding autoradiographic techniques were applied to analyze different constituents of these two systems and to study their locations relative to each other in grafts allowed to grow for 9–17 months following transplantation. For the cholinergic system, a modular organization was found in the striatal grafts with stains for choline acetyltransferase and acetylcholinesterase, respectively the synthetic and degradative enzymes for cholinergic neurons; by autoradiographic [³H] hemicholinium binding, specific for high affinity choline uptake sites associated with cholinergic terminals; and by autoradiographic [³H] pirenzepine binding, selective for M1 receptors. For the dopaminergic system, a comparable modular organization was found in the grafts by immunostaining for tyrosine hydroxylase, the catecholamine synthetic enzyme; by autoradiographic [³H] mazindol binding for dopamine uptake sites; and by [³H] SCH23390 binding for dopamine D1 receptors and [³H] sulpiride binding for dopamine D2 receptors. The results indicate that the distributions of the cholinergic and dopaminergic markers in striatal grafts are in close anatomical register. These markers for intracellular and membrane‐associated components of the cholinergic and dopaminergic systems were preferentially localized in the acetylcholesterase‐rich patches of the grafts in which cortical and thalamic fibers have also been found in striatal grafts, and in which output neurons projecting to the pallidum are located. This anatomical correlation suggests that the substrates for cholinergic‐dopaminergic interactions typical of the normal striatum may be reinstated in the grafts both in relation to efferent neurons establishing connections with the host brain that are typical of normal striatofugal connections, and in relation to major afferent fiber systems from the host brain originating in regions known to project densely to the normal striatum. Accordingly, the cholinergic and dopaminergic systems in such grafts may regulate the functional influence of the grafts on the behavior of host animals.