Cooperative synthesis of dopamine by non-dopaminergic neurons as a compensatory mechanism in the striatum of mice with MPTP-induced Parkinsonism

• Published in: Neurobiology of disease Vol. 98; pp. 108 - 121
• Main Authors: Kozina, Elena A, Kim, Aleksandr R, Kurina, Anna Y, Ugrumov, Michael V
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2017; Elsevier
• Subjects: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Aromatic l-amino acid decarboxylase; Aromatic-L-Amino-Acid Decarboxylases - metabolism; Corpus Striatum - metabolism; Corpus Striatum - pathology; Dopamine - biosynthesis; Dopamine beta-Hydroxylase - metabolism; Gyrus Cinguli - metabolism; Gyrus Cinguli - pathology; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning - metabolism; MPTP Poisoning - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Nigrostriatal system; Olfactory Bulb - metabolism; Olfactory Bulb - pathology; Parkinson's disease; RNA, Messenger - metabolism; Substantia Nigra - metabolism; Substantia Nigra - pathology; Tissue Culture Techniques; Tyrosine 3-Monooxygenase - metabolism; Tyrosine hydroxylase; norepinephrine; AADC; dopamine membrane transporter; 6-OHDA; l-3,4-dihydroxyphenylalanine; DBH; dopamine beta-hydroxylase; A romatic l-amino acid decarboxylase; FR; MPP; aromatic l-amino acid decarboxylase; T yrosine hydroxylase; serotonin; MAP2; high performance liquid chromatography with electrochemical detection; VMAT2; l-DOPA; SN; N igrostriatal system; substantia nigra; vesicular monoamine transporter 2; 1-methyl-4-phenylpyridinium; tyrosine hydroxylase; Parkinson ' s disease; 6-hydroxydopamine; Fluoro-Ruby; M ice; DAT; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NE; MPTP; ТН; 5-HT; DA; dopamine; microtubule-associated protein 2; HPLC-ED; Parkinson's disease; Aromatic l-amino acid decarboxylase; Tyrosine hydroxylase; Mice; Nigrostriatal system
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2016.12.005

Abstract Since the late 80s it has been repeatedly shown that besides dopaminergic neurons, the brain contains so-called monoenzymatic neurons possessing one of the enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic l -amino acid decarboxylase (AADC). However, the data on the existence of monoenzymatic neurons in the striatum remain controversial, and little is known about their functional significance. The aim of this study was to test our hypothesis that monoenzymatic TH-containing neurons produce DA in cooperation with the neurons containing AADC, which might help to compensate DA deficiency under the failure of the nigrostriatal dopaminergic system. Using a combination of techniques: retrograde tracing, qPCR and immunolabeling for TH, AADC and MAP2, we showed that the striatum of mice with normal and degraded dopaminergic system comprises of monoenzymatic TH- and AADC-containing neurons. To provide evidence for cooperative synthesis of DA, we used an ex vivo model of inhibiting of DA synthesis by blocking transport of l -DOPA, produced in monoenzymatic TH-containing neurons, to neurons containing AADC by means of l -leucine, a competitive inhibitor of the membrane transporter of large neutral amino acids, and l -DOPA. With this original approach, cooperative synthesis of DA in the striatum was proven in MPTP-treated mice but not in the control. Furthermore, we demonstrated that the proportion of DA produced through cooperative synthesis in the striatum of MPTP-treated mice increases as the degradation of dopaminergic system proceeds. An increase in the proportion of cooperative synthesis of DA alongside degradation of the dopaminergic system is also proved by an increase of both TH gene expression and the number of TH-immunoreactive structures in the striatum. Thus, these data suggest that the cooperative synthesis of DA in the degraded striatum is an up-regulated compensatory reaction, which plays an increasing role as DA deficiency rises, and might be considered among the principal mechanisms of neuroplasticity in neurodegenerative diseases.