title: Adaptive changes in the nigrostriatal pathway in response to increased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration in the mouse.
abstract: Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5-day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH-immunoreactive neurons (-70.2%) and striatal dopamine content (-38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.
authors.affiliation: Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. erwan.bezard@umr5543.u-bordeaux2.fr
authors.forename: E
authors.initials: E
authors.lastname: Bezard
authors.forename: M
authors.initials: M
authors.lastname: Jaber
authors.forename: F
authors.initials: F
authors.lastname: Gonon
authors.forename: A
authors.initials: A
authors.lastname: Boireau
authors.forename: B
authors.initials: B
authors.lastname: Bloch
authors.forename: C E
authors.initials: CE
authors.lastname: Gross
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D004558:Electric Stimulation; D003576:Electron Transport Complex IV / Q000378:metabolism; D004594:Electrophysiology; D006719:Homovanillic Acid / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology*; D013574:Synaptosomes / Q000378:metabolism; D014316:Tritium; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014316:Tritium; D015102:3,4-Dihydroxyphenylacetic Acid; D014446:Tyrosine 3-Monooxygenase; D003576:Electron Transport Complex IV; D004298:Dopamine; D006719:Homovanillic Acid