Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism.

Progressive degeneration of nigrostriatal dopaminergic (DA-ergic) neurons is a key component in the pathogenesis of Parkinson's disease, which develops for a long time at the preclinical stage with no motor dysfunctions due to the initiation of compensatory processes. The goal of this study was to evaluate the changes in surviving nigrostriatal DA-ergic neurons with focus on tyrosine hydroxylase (TH) in MPTP-treated mice at the presymptomatic and early symptomatic stages of parkinsonism. According to our data, a partial degeneration of DA-ergic neurons at the presymptomatic stage was accompanied by: (i) no change in TH mRNA content in the substantia nigra (SN) suggesting a compensatory increase of TH gene expression in individual neurons; (ii) a decrease of TH protein content in the nigrostriatal system and no change in individual neurons, suggesting a slowdown of TH translation. When comparing DA-ergic neurons at the early symptomatic stage and presymptomatic stage, it becomes evident: (i) a decrease of TH mRNA content in the SN and hence gene expression in individual neurons; (ii) a decrease of TH content in the striatum and its increase in the SN and individual neurons suggesting an acceleration of TH translation. TH activity, an index of the rate of DA synthesis, was unchanged in the SN and decreased in the striatum to the same degree at both stages of parkinsonism. In the meantime, TH activity in individual neurons appeared to be compensatory increased, but to a higher degree at the symptomatic stage than at the presymptomatic one. These data first show that DA depletion, which provokes motor dysfunction, is not a result of the decrease of TH activity and the rate of DA synthesis but is rather related to either a decrease of DA release or an increase of DA uptake in striatal DA-ergic axons.

High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease.

Chronic high frequency stimulation of the subthalamic nucleus (STN-HFS) efficiently alleviates motor symptoms of advanced Parkinson's disease (PD). Here, we looked for possible STN-HFS-induced changes on adult brain neurogenesis in the hippocampus and olfactory bulb that may be related to non-motor deficits associated to PD, such as mood disorders and olfaction deficits. Cell proliferation (Ki-67 immuno-positive-cells) and survival (bromodeoxyuridine (BrdU)-immuno-positive cells) were assessed in the subventricular zone-olfactory bulb continuum and the dentate gyrus of the hippocampus of hemiparkinsonian rats with or without continuous STN-HFS for 8 days. Dopamine lesion impaired cell proliferation and survival through different mechanisms, the effect on proliferation being correlated to the level of dopamine depletion whereas the effect on survival was not. Prolonged STN-HFS did not affect cell proliferation, but increased cell survival bilaterally. In these regions of constitutive neurogenesis, the percentage of new neuroblasts (BrdU-doublecortin-positive cells) was unchanged, suggesting that STN-HFS can lead to a net increase in newly formed neurons later on. STN-HFS also increased new cell survival in the striatum and promoted dopamine system recovery detected by tyrosine hydroxylase immunostaining. These data provide the first evidence that prolonged STN-HFS has a neurorestorative action and support the view that the action of this neurosurgical treatment can bypass the cortico-basal ganglia-thalamocortical loop circuits and largely impinge neuroplasticity and brain function.

Different functional basal ganglia subcircuits associated with anti-akinetic and dyskinesiogenic effects of antiparkinsonian therapies.

Subthalamic nucleus high frequency stimulation (STN-HFS) efficiently alleviates L-DOPA-sensitive parkinsonian motor symptoms, but has no direct beneficial action on L-DOPA-induced dyskinesias (LID). Here, we provide evidence that anti-akinetic STN-HFS or dyskinesiogenic L-DOPA similarly reversed the dopamine lesion-induced increases in gene expression of cytochrome oxidase subunit I (CoI), a metabolic marker of neuronal activity, in the globus pallidus, STN and substantia nigra pars reticulata (SNr) in rats. In contrast, in entopeduncular nucleus (EP), STN-HFS did not modify the lesion-induced increase in CoI mRNA levels, whereas L-DOPA induced a marked decrease versus control. Combining the two treatments did not reveal significant interaction. Interestingly, CoI gene expression in EP but not in SNr was inversely correlated with striatal preprodynorphin mRNA level, a LID marker. This work suggests the existence of two functional basal ganglia subcircuits: the one, including STN and SNr, involved in antiparkinsonian action, and the other, including EP, preferentially involved in LID.