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      Striatonigral neurons divide into two distinct morphological-physiological phenotypes after chronic L-DOPA treatment in parkinsonian rats

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          Abstract

          Dendritic regression of striatal spiny projection neurons (SPNs) is a pathological hallmark of Parkinson’s disease (PD). Here we investigate how chronic dopamine denervation and dopamine replacement with L-DOPA affect the morphology and physiology of direct pathway SPNs (dSPNS) in the rat striatum. We used a lentiviral vector optimized for retrograde labeling (FuG-B-GFP) to identify dSPNs in rats with 6-hydroxydopamine (6-OHDA) lesions. Changes in morphology and physiology of dSPNs were assessed through a combination of patch-clamp recordings and two photon microscopy. The 6-OHDA lesion caused a significant reduction in dSPN dendritic complexity. Following chronic L-DOPA treatment, dSPNs segregated into two equal-sized clusters. One group (here called “cluster-1”), showed sustained dendritic atrophy and a partially normalized electrophysiological phenotype. The other one (“cluster-2”) exhibited dendritic regrowth and a strong reduction of intrinsic excitability. Interestingly, FosB/∆FosB induction by L-DOPA treatment occurred preferentially in cluster-2 dSPNs. Our study demonstrates the feasibility of retrograde FuG-B-GFP labeling to study dSPNs in the rat and reveals, for the first time, that a subgroup of dSPNs shows dendritic sprouting in response to chronic L-DOPA treatment. Investigating the mechanisms and significance of this response will greatly improve our understanding of the adaptations induced by dopamine replacement therapy in PD.

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          Most cited references39

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          Neurotransmitters and neuromodulators in the basal ganglia.

          The basal ganglia have become a focus for work on neurotransmitter interactions in the brain. These structures contain a remarkable diversity of neuroactive substances, organized into functional subsystems that have unique developmental histories and vulnerabilities in neurodegenerative diseases. A new view of the basal ganglia is emerging on the basis of this neurochemical heterogeneity, suggesting that dynamic regulation of transmitter expression may be a key to extrapyramidal function.
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            Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease.

            Golgi impregnations of neostriatum from deceased Huntington's disease patients and controls were examined. In all cases of Huntington's disease the morphology of dendrites of medium-sized spiny neurons was markedly altered by the appearance of recurved endings and appendages, a decrease or increase in the density of spines, and abnormalities in the size and shape of spines. Pathological changes were rarely observed in medium-sized and large aspiny neostriatal neurons. The findings provide evidence for simultaneous degeneration and growth of spiny neurons in Huntington's disease and support the view that a specific population of neostriatal neurons is selectively involved in its pathogenesis.
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              Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia

              Summary The striatum is widely viewed as the fulcrum of pathophysiology in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In these disease states, the balance in activity of striatal direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs) is disrupted, leading to aberrant action selection. However, it is unclear whether countervailing mechanisms are engaged in these states. Here we report that iSPN intrinsic excitability and excitatory corticostriatal synaptic connectivity were lower in PD models than normal; L-DOPA treatment restored these properties. Conversely, dSPN intrinsic excitability was elevated in tissue from PD models and suppressed in LID models. Although the synaptic connectivity of dSPNs did not change in PD models, it fell with L-DOPA treatment. In neither case, however, was the strength of corticostriatal connections globally scaled. Thus, SPNs manifested homeostatic adaptations in intrinsic excitability and in the number but not strength of excitatory corticostriatal synapses.
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                Author and article information

                Contributors
                Tim.Fieblinger@med.lu.se
                Angela.Cenci-Nilsson@med.lu.se
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                3 July 2018
                3 July 2018
                2018
                : 8
                : 10068
                Affiliations
                [1 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, , Lund University, ; Lund, Sweden
                [2 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, CNS Gene Therapy, Department of Experimental Medical Science, , Lund University, ; Lund, Sweden
                [3 ]ISNI 0000 0004 0562 3952, GRID grid.452925.d, Wissenschaftskolleg zu Berlin, , Institute for Advanced Study, ; Wallotstr. 19, D-14193 Berlin, Germany
                [4 ]Institute of Pharmacy, Pharmacology and Toxicology, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria
                [5 ]ISNI 0000 0001 2106 639X, GRID grid.412041.2, CNRS, Institut des Maladies Neurodégénératives, , University of Bordeaux, ; Bordeaux, France
                Author information
                http://orcid.org/0000-0002-3040-6074
                Article
                28273
                10.1038/s41598-018-28273-5
                6030109
                29968767
                917ece21-6890-4379-8b59-84f381a085da
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 March 2018
                : 18 June 2018
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