Neurotransmitter-related gene expression in intrastriatal striatal transplants. III. Regulation by host cortical and dopaminergic afferents.

Abstract

Grafted striatal neurons have previously been shown to receive innervation from both the host cerebral cortex and dopaminergic substantia nigra. In the present study, we have used quantitative in situ hybridization histochemistry for striatal neuropeptide mRNAs, to determine the extent of functional integration exhibited by these two afferent systems. DARPP-32, preproenkephalin (PPE) and preprotachykinin (PPT) mRNAs were all expressed within discrete patches of the graft (termed P-regions) which corresponded well with each other on adjacent sections. Dopamine-depleting 6-OHDA lesions resulted in a marked increase in PPE mRNA levels and a concomitant decrease in PPT mRNA expression both in the remaining host striatum and in the P-regions of the graft. In a previous report [7], we have shown that cortical and dopaminergic afferents to the striatum interact in the regulation of PPE mRNA expression, such that in the absence of functional dopaminergic inputs, intact prefrontal corticostriatal afferents are necessary in order to maintain increased PPE mRNA levels. In the present study, we observed that cortical knife cut lesions placed at the level of the foreceps minor in previously 6-OHDA-lesioned animals resulted in a normalization of PPE mRNA expression, not only in the remaining host striatum but also within the P-regions of striatal grafts. Cellular analysis showed that this normalization was most pronounced in the peripherally situated P-regions (along the graft borders), which are known to receive dense host-derived cortical input. The cortical lesions had no significant effect on the 6-OHDA-induced reduction of PPT mRNA levels neither in the remaining lost striatum nor in the striatal graft. The expression of DARPP-32 mRNA in the remaining host striatum or striatal graft was not affected by either 6-OHDA lesion or cortical transection, demonstrating the specificity of the cortical lesion effect. These results indicate that both cortical and dopaminergic afferents originating in the host, functionally regulate neuropeptide mRNA expression within the striatal grafts, and that the two afferent systems interact with each other in the regulation of enkephalin gene expression in grafted neurons. On basis of recent results [9] showing that the enkephalin-expressing neurons are identical, at least in part, to efferent graft neurons projecting to the host globus pallidus, it is proposed that the cortical-dopamine interaction demonstrated here may play an important role in the recovery of complex motor performance induced by the striatal transplants.