DARPP-32-rich zones in grafts of lateral ganglionic eminence govern the extent of functional recovery in skilled paw reaching in an animal model of Huntington's disease.

Abstract

Grafts of striatal tissue comprise two different types of tissue: regions with (P-zones) and without (NP-zones) neurons that express markers characteristic of the striatum, such as dopamine- and cyclic AMP-regulated phosphoprotein with a mol. wt of 32,000 (DARPP-32). It remains unclear whether P-zones alone play a crucial role in functional effects of striatal grafts in an animal model of Huntington's disease. The present study has been performed to determine: (i) the yield of DARPP-32-positive neurons in grafts of lateral ganglionic eminence; (ii) whether treatment of graft tissue with the spin-trapping agent alpha-phenyl-tert-butyl nitrone enhances the survival of implanted DARPP-32-positive neurons; and (iii) the relationship between the number of DARPP-32-positive neurons in the grafts and functional effects of the grafts on paw-reaching ability in rats with unilateral quinolinic acid lesions of the striatum. Dissociated tissue derived from the lateral ganglionic eminence of rat embryos (embryonic day 14), with or without addition of alpha-phenyl-tert-butyl nitrone (3 mM), was implanted into the quinolinic acid-lesioned striatum. Compared to unlesioned normal animals, rats with striatal lesions showed substantial impairment in paw-reaching ability, particularly on the side contralateral to the lesion, as judged from the number of pellets retrieved by each paw. Intrastriatal grafts gave rise to a significant improvement in paw-reaching ability. The mean total number of surviving DARPP-32-positive cells in grafts without alpha-phenyl-tert-butyl nitrone treatment was estimated at 115 x 10(3), which did not significantly differ from that in alpha-phenyl-tert-butyl nitrone-treated grafts. The paw-reaching scores were significantly correlated with the volumes of P-zones and the number of DARPP-32-positive neurons, but with neither the volumes of NP-zones nor the total graft volume. The results suggest that P-zones in striatal grafts mediate graft-derived functional recovery in a complex task such as skilled forelimb use. Although the antioxidant treatment with alpha-phenyl-tert-butyl nitrone failed to promote graft survival, the positive correlation between the yield of DARPP-32-positive cells in the graft and the extent of the functional recovery highly warrants further attempts to increase the yield of the striatal component in the graft.