Tyrosine hydroxylase cells appearing in the mouse striatum after dopamine denervation are likely to be projection neurones regulated by l‐DOPA

Abstract

Tyrosine hydroxylase (TH)-immunoreactive (ir) neurones are detected in the striatum of animals after dopamine depletion and also in human parkinsonian patients. Although there is extensive evidence for TH-ir neurones in the lesioned rodent striatum, there are few details regarding the molecular phenotype of these neurones, regulation of their TH expression after l-3,4-dihydroxyphenylalanine (L-DOPA) treatment and their function. In the present study, we examined the time-course of appearance of TH-ir neurones in the mouse striatum after 6-hydroxydopamine (6-OHDA) lesion and determined their molecular phenotype. We found that TH-ir neurones appeared in the striatum as early as 3 days after a 6-OHDA lesion. By 1 week after the lesion, the number of TH-ir neurones started to decrease and this decrease progressed significantly over time. Treatment with L-DOPA increased both the number of TH-ir neurones and the intensity of their immunolabelling. The TH-ir neurones that appear after the 6-OHDA lesion in the striatum are not newly generated cells as they did not incorporate 5-bromo-2-deoxyuridine. We found that the vast majority of TH-ir neurones colocalized with dynorphin and enkephalin, suggesting that they are projection neurones of the direct and indirect striatal output pathways. TH-ir neurones did not express the dopamine transporter but half of them expressed amino acid decarboxylase, an enzyme required for dopamine synthesis. Finally, striatal TH-ir neurones are functionally active, expressing the neuronal activation marker FosB in response to L-DOPA treatment. Promotion of these striatal TH-ir neurones may be beneficial in Parkinson's disease, particularly in the early stages when dopamine denervation is incomplete.

Non-dopaminergic neurons partly expressing dopaminergic phenotype: Distribution in the brain, development and functional significance

“…So far, all the attempts to show that the striatal monoenzymatic TH neurons can be originated in adulthood from the brain stem cells under certain circumstances, e.g. in aged monkeys in norm and in monkeys and mice under degeneration of nigral DA-ergic neurons, were unsuccessful (Tandé et al, 2006;Darmopil et al, 2008).…”

Activation of DREAM (Downstream Regulatory Element Antagonistic Modulator), a Calcium-Binding Protein, Reduces L-DOPA-Induced Dyskinesias in Mice

“…Animals received unilateral stereotaxic injections (2 x 2 µl) of 6-OHDA-HBr (20 mM, containing 0.02% ascorbic acid; Sigma-Aldrich) as described previously (39).…”

Methamphetamine Causes Degeneration of Dopamine Cell Bodies and Terminals of the Nigrostriatal Pathway Evidenced by Silver Staining

“…An image analysis system (Analytical Imaging Station; Imaging Research, Linton, UK) was used to convert color intensities into a gray scale and to quantify the area of staining in the striatum as a proportion of pixels in the striatum that show staining (stained area) in relation to total pixels in the striatum (scanned area). We refer to this as proportional stained area (Darmopil et al, 2008(Darmopil et al, , 2009. The threshold was chosen in saline animals and applied to all animals.…”