Elsevier

Neuroscience

Volume 193, 13 October 2011, Pages 310-322
Neuroscience

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Functional reorganization of the presynaptic dopaminergic terminal in parkinsonism

https://doi.org/10.1016/j.neuroscience.2011.07.029Get rights and content

Abstract

Whether dopamine (DA) release is compensated during the presymptomatic phase of Parkinson's disease (PD) is controversial. Here we use in vivo voltammetry in the parkinsonian rat and an electrical stimulation protocol established to fatigue nigrostriatal dopaminergic (DAergic) neurons to investigate the plasticity of DA-release mechanisms. Amplitudes of evoked voltammetric signals recorded in intact rat striata decreased with repetitive, high-frequency stimulation (60 Hz, every 5 min/60 min). Strikingly, DA levels were maintained during an identical “fatiguing” protocol in 6-hydroxydopamine-lesioned (<40% denervation) striata in the absence of enhanced DA synthesis. In contrast, more severely lesioned striata (>55% denervation) also appeared to sustain DA release, however, this was demonstrated in the presence of enhanced synthesis. Sustained release was replicated in intact animals after irreversible blockade of the dopamine transporter (DAT) via RTI-76, implicating neuronal uptake as a trigger. We further demonstrate through kinetic analysis that lesions and compromised uptake target a “long-term” (time constant of minutes) presynaptic depression, which underlies the maintenance of release. Taken together, our findings identify a denervation-induced maintenance of DA release that was independent of activated synthesis and driven by altered uptake. This novel neuroadaptation may contribute to early preclinical normalization of function and help resolve discrepant findings regarding compensatory changes in DA release during progression of the parkinsonian state.

Highlights

▶1. First in vivo report of central compensatory mechanism in presymptomatic parkinsonism. ▶2. Sustained dopamine release in early preclinical stage is independent of synthesis. ▶3. Sustained dopamine release is mimicked by irreversible uptake inhibition. ▶4. Sustained release is modeled by eliminating long-term presynaptic depression. ▶5. First comparison of major kinetic models for dopamine release in parkinsonism.

Section snippets

Experimental design

Three experimental designs were employed in the present study. The 6-OHDA unilateral partial lesion model was utilized to generate all parkinsonian rats for two of the designs. The first design consisted of two groups and examined synthesis rates in lesioned and intact rats by administering the dopa-decarboxylase inhibitor NSD-1015. The second design examined time-dependent DA release utilizing the fatigue stimulation protocol both before and after depletion of the releasable pool of DA via the

Time-dependent DA release dynamics

The present study employed a fatiguing protocol, in which pulse trains were applied more frequently in order to elicit a time-dependent DA release that decreased over time (Michael et al., 1987, Yavich, 1996, Montague et al., 2004). Voltammetric traces collected in an intact rat exemplify this time-dependent decrease in release (Fig. 1A, top). Evoked signals consist of an upward slope, which coincides with stimulus application and whose amplitude reflects DA release, and a downward slope after

Discussion

The central neuroadaptation proposed for the presymptomatic phase of PD, a compensatory maintenance of DA release, has been demonstrated in the following study by using a direct measure of DA release as indicated by decreased fatigue rates of DA release and through kinetic analysis. It thus appears that components of striatal DA release differentially respond to partial DA depletion, with time-dependent, but not time-independent, mechanisms adapting. Our data also suggest that maintaining

Conclusion

We establish a novel compensatory maintenance of DA release suggestive of a functional reorganization of the presynaptic DAergic terminal in the early parkinsonian state. Taken together, our results have broad implications for the neuroadaptation, progression, and treatment of PD.

Acknowledgments

This research was supported by National Institutes of Health grant NS 35298–02 and 03 (P.A.G.). We kindly thank Kim Garris, Rebecka Jansson, Sandie Rokosik, and Sara Takacs for technical assistance.

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    These authors contributed equally to this work.

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