Postpubertal manifestations of dopaminergic hyperactivity following neonatal lesions of the mediodorsal thalamic nuclei

Abstract

The acute and long-term changes following large neostriatal ibotenic acid lesions and intrastriatal striatal neuronal grafting have been studied neurochemically by determinations of the γ-aminobutyrate (GABA) and acetylcholine-synthetic enzymes, glutamate decarboxylase and choline acetyltransferase, and of dopamine and its primary acidic metabolite, 3,4-dihydroxyphenylacetic acid. The neurochemical data have been matched with estimates of tissue volume changes and striatal graft development through tissue weight and protein content analysis and histological volumetric measurements.Injections of 20 μg ibotenic acid, deposited over four injection sites in the head of the caudate-putamen, had by one week caused a 70–85% reduction in glutamate decarboxylase and choline acetyltransferase activity. With time there was a progressive recovery of the specific enzyme activities in the lesioned areas (expressed per μg protein or per mg wet weight) to 40–60% of control levels as determined at 20 weeks post-lesion in the caudate-putamen. This increase was, however, largely if not exclusively due to the long-term shrinkage of the lesioned caudate-putamen, amounting to 50–70% at 20 weeks. Thus, the total glutamate decarboxylase and choline acetyltransferase activity levels in the lesioned caudate-putamen remained virtually unchanged (between 15 and 25% of control) over the 20 week experimental period. Glutamate decarboxylase activity was also markedly reduced (35–70%) in the two primary striatal projection areas, globus pallidus and substantia nigra, and there were no signs of recovery over time. Striatal dopamine levels, which were acutely unaffected by the lesion, showed a slow decline so that the total dopamine content in the area was reduced by about 80% at 20 weeks.Suspended striatal neurons obtained from the striatal primordia of 14–15-day-old rat fetuses, injected into the previously lesioned caudate-putamen, survived and established a new striatum-like structure at the site of the ibotenic acid lesion. The final volume of the graft tissue reached up to about 10 mm3 in volume and reduced striatal atrophy on average from about 50 to 70% of normal control in the rats with lesions to about 30–40% in the animals with grafts. In the rats with grafts, there was a significant recovery of glutamate decarboxylase and choline acetyltransferase activities not only in the lesioned caudateputamen, containing the graft (from 20–25% to 40–50%, when expressed as total enzyme activity levels), but also the glutamate decarboxylase activity in the globus pallidus, a structure located at a distance from the graft. These observations indicate that both GABAergic and cholinergic neurons survive in large numbers in the grafts (equivalent to perhaps one-third to one-fourth of the numbers normally present in the head of the caudate-putamen), and that the GABAergic neurons in the graft may be capable of reinnervating the initially denervated globus pallidus.It is proposed that the intrastriatal striatal grafts are able to restore GABAergic inhibitory control in the ibotenate-lesioned neuronal circuitry and that this mechanism may be important or even necessary for the mediation of graft-induced behavioural recovery in the animals with lesions.