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

TY - JOUR

T1 - Striatonigral neurons divide into two distinct morphological-physiological phenotypes after chronic L-DOPA treatment in parkinsonian rats

AU - Fieblinger, T

AU - Zanetti, L

AU - Sebastianutto, I

AU - Breger, L S

AU - Quintino, L

AU - Lockowandt, M

AU - Lundberg, C

AU - Cenci, M A

PY - 2018/7/3

Y1 - 2018/7/3

N2 - 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.

AB - 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.

KW - Animals

KW - Corpus Striatum/metabolism

KW - Disease Models, Animal

KW - Dopamine/metabolism

KW - Dyskinesia, Drug-Induced/metabolism

KW - Female

KW - Levodopa/pharmacology

KW - Mice

KW - Mice, Transgenic

KW - Neostriatum/metabolism

KW - Neurons/pathology

KW - Parkinson Disease/physiopathology

KW - Phenotype

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Dopamine D1/metabolism

KW - Striatonigral Degeneration/physiopathology

U2 - 10.1038/s41598-018-28273-5

DO - 10.1038/s41598-018-28273-5

M3 - SCORING: Journal article

C2 - 29968767

VL - 8

SP - 10068

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -