ALTERATIONS IN TYROSINE-HYDROXYLASE EXPRESSION FOLLOWING PARTIAL LESIONS OF THE NIGROSTRIATAL BUNDLE

Effects of destruction of central dopaminergic neurons on tyrosine hydroxylase gene expression were investigated. Two weeks after the unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, a 67% to 99% loss of striatal dopamine (DA) content was observed ipsilateral to the injection site. Measures of tyrosine hydroxylase (TH) protein levels revealed losses in striatal content proportional to DA content. Striatal dihydroxylphenylacetic acid (DOPAC) was somewhat less affected, resulting in 2- to 4-fold increases in the striatal DOPAC/DA ratio, depending on the severity of the lesion. Morphologically, surviving TH-positive substantia nigra pars compacta (SNc) neurons were more rounded than contralateral control cells, and exhibited decreases in cross-sectional area that were proportional to the loss of striatal DA. Measures of cytoplasmic TH mRNA levels in surviving neurons by in situ hybridization autoradiography revealed a significant 23% decrease in TH content per cell that could be correlated to lesion size. The decreases in cross-sectional area and TH mRNA content resulted in a small decrease in TH mRNA density of 6%. The determination of TH transcription rate by an intron-directed in situ hybridization assay found no significant change in TH transcriptional activity as a function of lesion. We conclude that the short-term effect of partial 6-OHDA-induced lesions of the nigrostriatal dopaminergic pathway is the selective loss or shrinkage of large DA neurons of the SNc, and that the associated down-regulation of TH mRNA expression in surviving neurons is due to a post-transcriptional mechanism related either to concomitant cellular hyperactivity or is secondary to the morphological alterations.