Striatonigral neurons divide into two distinct morphological-physiological phenotypes after chronic L-DOPA treatment in parkinsonian rats
Sci Rep. 2018-07-03; 8(1):
DOI: 10.1038/s41598-018-28273-5
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1. Sci Rep. 2018 Jul 3;8(1):10068. doi: 10.1038/s41598-018-28273-5.
Striatonigral neurons divide into two distinct morphological-physiological
phenotypes after chronic L-DOPA treatment in parkinsonian rats.
Fieblinger T(1)(2), Zanetti L(3)(4), Sebastianutto I(3), Breger LS(5)(6),
Quintino L(5), Lockowandt M(5), Lundberg C(5), Cenci MA(7).
Author information:
(1)Basal Ganglia Pathophysiology Unit, Department of Experimental Medical
Science, Lund University, Lund, Sweden. .
(2)Wissenschaftskolleg zu Berlin, Institute for Advanced Study, Wallotstr. 19,
D-14193, Berlin, Germany. .
(3)Basal Ganglia Pathophysiology Unit, Department of Experimental Medical
Science, Lund University, Lund, Sweden.
(4)Institute of Pharmacy, Pharmacology and Toxicology, Center for Molecular
Biosciences, University of Innsbruck, Innsbruck, Austria.
(5)CNS Gene Therapy, Department of Experimental Medical Science, Lund University,
Lund, Sweden.
(6)CNRS, Institut des Maladies Neurodégénératives, University of Bordeaux,
Bordeaux, France.
(7)Basal Ganglia Pathophysiology Unit, Department of Experimental Medical
Science, Lund University, Lund, Sweden. .
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.
DOI: 10.1038/s41598-018-28273-5
PMCID: PMC6030109
PMID: 29968767