Adaptive changes in the nigrostriatal pathway in response to increased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration in the mouse

Although several adaptive mechanisms have been identified that mask the exi stence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remai n an enigma. In order to examine: (i) the nature of the dopaminergic adapti ve mechanisms that come into action; (ii) their sequential activation in re lation to the severity of degeneration; and (iii) their efficacy with regar d to the maintenance of a normal level of basal ganglia activity, we analys ed the brains of mice treated daily with 1-methyl-4-phenyl-1,2,3,6-tetrahyd ropyridine (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 compen satory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) pr otein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH-immu noreactive 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 maintai n striatal dopaminergic homeostasis is also illustrated by an increase in t he cytochrome oxidase activity of substantia nigra pars reticulata, a marke r of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we pres ent from our MPTP mice model infirm this hypothesis. This study explores th e link between the degree of nigral degeneration and the sequential activat ion of dopaminergic compensatory mechanisms in the nigrostriatal pathway an d, in so doing, proposes a rethink of the paradigm applied to these mechani sms.