Rajakumar N, Rushlow W, Rajakumar B, Naus C C, Stoessl A J, Flumerfelt B A
Department of Anatomy and Cell Biology, University of Western Ontario, London, Canada.
Neuroscience. 1997 Feb;76(4):1173-85. doi: 10.1016/s0306-4522(96)00379-x.
Fetal dopaminergic neurons grafted into the dopamine-depleted striatum have previously been shown to normalize neurochemical and behavioural abnormalities. However, the extent of graft-induced recovery of striatal compartments, which differ in their ontogeny, neurochemical properties and function, is still not clear. The striosome and matrix compartments of the striatum provide a segregated projection to somatostatin-containing GABAergic neurons of the rostral part of the entopeduncular nucleus and somatostatin-negative GABAergic neurons of the caudal part of the entopeduncular nucleus, respectively. In the present study, preprosomatostatin and glutamate decarboxylase messenger RNA levels in the rostral and caudal parts of the entopeduncular nucleus were determined six and 18 months postgrafting in rats with complete recovery of rotational behaviour following apomorphine challenge, and in rats with unilateral 6-hydroxydopamine lesions or sham lesions and no grafts. Sections were processed for in situ hybridization using 35S-labelled cRNA probes for glutamate decarboxylase (67,000 mol. wt isoform; GAD67) and preprosomatostatin. Autoradiographs showed a marked increase in preprosomatostatin messenger RNA within the ipsilateral entopeduncular nucleus in 6-hydroxydopamine-lesioned rats, and a substantially lower increase six months postgrafting. At 18 months postgrafting, the preprosomatostatin messenger RNA levels were symmetrical within the entopeduncular nucleus. Unilateral depletion of striatal dopamine resulted in a moderate increase in GAD67 messenger RNA levels within the ipsilateral entopeduncular nucleus, along with a substantial decrease in GAD67 levels within the contralateral nucleus. By six months postgrafting, the GAD67 levels had decreased considerably within the ipsilateral entopeduncular nucleus, while the messenger RNA levels had returned to normal within the contralateral nucleus. Interestingly, at 18 months postgrafting, the GAD67 levels remained decreased within the ipsilateral entopeduncular nucleus and were significantly lower than the normal value. The results indicate that fetal nigral grafts placed within the dopamine-depleted striatum can restore the neurochemical alterations seen in striatal target areas such as the entopeduncular nucleus. This may form the neurochemical basis of graft-induced behavioural recovery, as the normalization of neurotransmitter messenger RNA levels in the entopeduncular nucleus reflects the restoration of overall activity in both direct and indirect striatal output pathways. The results also indicate that the graft-derived dopaminergic innervation restores the output of both striosome and matrix compartments of the striatum. The present results also showed a progressive recovery leading to over-compensation of neurotransmitter messenger RNA levels following grafting, perhaps indicating the importance of feedback regulation of grafted dopaminergic neurons by the host.
