Presymptomatic compensation in Parkinson's disease is not dopamine-mediated

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Abstract

The symptoms of Parkinson's disease (PD) appear only after substantial degeneration of the dopaminergic neuron system (e.g. an 80% depletion of striatal dopamine) – that is, there is a substantive presymptomatic period of the disease. It is widely believed that dopamine-related compensatory mechanisms are responsible for delaying the appearance of symptoms. Recent advances in understanding the presymptomatic phase of PD have increased our understanding of these dopamine-related compensatory mechanisms and have highlighted the role of non-dopamine-mediated mechanisms both within and outside the basal ganglia. This increased knowledge of plasticity within cortical–basal-ganglia–thalamocortical circuitry as dopaminergic neuron degeneration progresses has implications for understanding plasticity in neural circuits generally and, more specifically, for developing novel therapeutics or presymptomatic diagnostics for PD.

Section snippets

Adaptive properties of dopaminergic neurons might not play a role in presymptomatic compensation in PD

In vivo assessment of electrically elicited levels of extracellular dopamine measured by fast-scan cyclic voltammetry has demonstrated that normal concentrations of extracellular dopamine are preserved in the partially denervated striatum without any significant active compensatory changes in dopamine uptake or release [10]. Thus, kinetic analysis of voltammetric recordings reveals that the concentration of dopamine released per stimulus pulse and the maximal rate of dopamine uptake decreases

A role for increased dopamine metabolism as a mechanism of presymptomatic compensation in PD appears unlikely

It has been recognized for many years that established PD is associated with increases in several markers of dopamine-mediated transmission (e.g. D2 receptors and dopamine metabolism, as assessed by the ratio of dopamine to its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid [6]). It was suggested that such upregulation of dopamine-mediated transmission might be a mechanism that attempted to compensate for dopamine loss in PD. In fact, in the progressive MPTP-lesioned primate

D2-receptor upregulation might represent a mechanism that compensates for progressive dopamine loss in PD

Studies in the progressive MPTP-lesioned primate demonstrate that the relationship between D2 receptor levels, degree of dopamine cell loss and symptoms is more complex than had been anticipated (Fig. 1a). Indeed, the relationship between D2 -like receptor binding and both DAT binding and dopamine content might be represented by second-order polynomial equations [13] (Fig. 1b), implying synergistic actions of two first-order processes. D2-like receptors are located on both the presynaptic

Upregulated enkephalin expression might represent a mechanism compensating for progressive dopamine loss in PD

GABAergic efferents from the striatum to the globus pallidus pars externalis (GPe) are overactive in the MPTP-lesioned primate model of PD [25]. This increased inhibition of GPe is generally assumed to play a major role in the genesis of parkinsonian symptoms by reducing activity in the inhibitory pallidosubthalamic pathway, which leads to disinhibition of the subthalamic nucleus (STN) and, thus, overactivity of basal ganglia outputs from the internal segment of the globus pallidus (GPi) and

Presymptomatic increases in the electrophysiological activity of STN and GPi could compensate for progressive loss of dopamine in PD

Although the notion that levels of gene expression are tightly coupled to levels of physiological activity is simplistic, the presymptomatic increase in PPE-A expression levels is nonetheless suggestive of changes in the activity of striatal medium spiny neurons before symptoms appear. The issue of presymptomatic changes in the electrophysiological activity of basal ganglia nuclei has thus emerged. Changes in activity in the STN and in GPi have been assessed, using multiunit

Structures outside the basal ganglia might compensate for progressive loss of dopamine in PD

The 2-deoxyglucose (2-DG) metabolic tracing technique was used during the 1980s to identify the changes in basal ganglia activity that were responsible for the generation of symptoms 25, 45, 46, 47, 48. The same technique has been applied to identify changes in neuronal metabolic activity that occur before and after the appearance of parkinsonian motor abnormalities in the MPTP model that recapitulates the progression of the disease [49]. This study focused on the basal ganglia, the motor

As yet unidentified mechanisms compensate for progressive loss of dopamine in PD

It seems likely that mechanisms regulating the transfer of information from basal ganglia output to the SMA, through the thalamus, would participate to compensate for abnormalities in basal ganglia outflow and so prevent the appearance of symptoms in the presymptomatic state. It remains to be determined where this compensation takes place. Four hypotheses can be proposed to explain why SMA activity is normal in presymptomatic animals with apparent major dysfunction of the basal ganglia: (1)

Concluding remarks

Recent advances in understanding changes in neural function as degeneration of dopaminergic cell loss progresses have shown the existence of a dissociation between three classes of events associated with PD that until now were considered to occur simultaneously. An emerging understanding suggests a sequential activation of three families of compensatory mechanisms, which leads us to consider that the presymptomatic period in PD in fact comprises three stages of increased compensatory intensity (

Acknowledgements

Our work is supported by INSERM (E.B) and University Victor Segalen-Bordeaux 2 (C.E.G.).

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