Tyrosine hydroxylase cells appearing in the mouse striatum after dopamine denervation are likely to be projection neurones regulated by L-DOPA.
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.
Darmopil
Sanja
S
Cajal Institute, Consejo Superior de Investigaciones Científicas, Avda Dr Arce 37, 28002 Madrid, Spain.
Muñetón-Gómez
Vilma C
VC
de Ceballos
María L
ML
Bernson
Miya
M
Moratalla
Rosario
R
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001973:Bromodeoxyuridine; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D003714:Denervation; D004298:Dopamine / Q000096:biosynthesis / Q000172:deficiency*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007980:Levodopa / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D018847:Opioid Peptides / Q000378:metabolism; D016627:Oxidopamine; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D015415:Biomarkers; D050483:Dopamine Plasma Membrane Transport Proteins; C483819:Fosb protein, mouse; D018847:Opioid Peptides; D016760:Proto-Oncogene Proteins c-fos; D013565:Sympatholytics; D007980:Levodopa; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001973:Bromodeoxyuridine; D004298:Dopamine