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Neurotox Res. 2016 Apr;29(3):364-80. doi: 10.1007/s12640-015-9557-5. Epub 2015 Sep 24.

CX3CR1 Disruption Differentially Influences Dopaminergic Neuron Degeneration in Parkinsonian Mice Depending on the Neurotoxin and Route of Administration.

Author information

1
Sorbonne Université UPMC UM75 INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Thérapeutique Expérimentale de la neurodégénérescence, Hôpital de la Salpêtrière - Bâtiment ICM, 47 boulevard de l'Hôpital, 75651, Paris, France.
2
Department of Morphology, Physiology and Basic Pathology (MFPb-Fisiologia), School of Odontology, University of Sao Paulo (USP), Av Café s/n 14040-220, Ribeirão Preto, SP, Brazil.
3
Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Preto, Brazil.
4
Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
5
Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
6
Department of Molecular Physiology, University of Saarland, Homburg, Germany.
7
INSERM UMR S894, Université Pierre et Marie Curie, UPMC, Paris, France.
8
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Campus Trindade, Florianópolis, SC, Brazil.
9
Department of Morphology, Physiology and Basic Pathology (MFPb-Fisiologia), School of Odontology, University of Sao Paulo (USP), Av Café s/n 14040-220, Ribeirão Preto, SP, Brazil. eadelbel@forp.usp.br.
10
Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Preto, Brazil. eadelbel@forp.usp.br.
11
Sorbonne Université UPMC UM75 INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Thérapeutique Expérimentale de la neurodégénérescence, Hôpital de la Salpêtrière - Bâtiment ICM, 47 boulevard de l'Hôpital, 75651, Paris, France. ritaraisman@gmail.com.

Abstract

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons accompanied by an inflammatory reaction. The neuron-derived chemokine fractalkine (CX3CL1) is an exclusive ligand for the receptor CX3CR1 expressed on microglia. The CX3CL1/CX3CR1 signaling is important for sustaining microglial activity. Using a recently developed PD model, in which the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin is delivered intranasally, we hypothesized that CX3CR1 could play a role in neurotoxicity and glial activation. For this, we used CX3CR1 knock-in mice and compared results with those obtained using the classical PD models through intraperitonal MPTP or intrastriatal 6-hydroxydopamine (6-OHDA). The striatum from all genotypes (CX3CR1(+/+), CX3CR1(+/GFP) and CX3CR1-deficient mice) showed a significant dopaminergic depletion after intranasal MPTP inoculation. In contrast to that, we could not see differences in the number of dopaminergic neurons in the substantia nigra of CX3CR1-deficient animals. Similarly, after 6-OHDA infusion, the CX3CR1 deletion decreased the amphetamine-induced turning behavior observed in CX3CR1(+/GFP) mice. After the 6-OHDA inoculation, a minor dopaminergic neuronal loss was observed in the substantia nigra from CX3CR1-deficient mice. Distinctly, a more extensive neuronal cell loss was observed in the substantia nigra after the intraperitoneal MPTP injection in CX3CR1 disrupted animals, corroborating previous results. Intranasal and intraperitoneal MPTP inoculation induced a similar microgliosis in CX3CR1-deficient mice but a dissimilar change in the astrocyte proliferation in the substantia nigra. Nigral astrocyte proliferation was observed only after intraperitoneal MPTP inoculation. In conclusion, intranasal MPTP and 6-OHDA lesion in CX3CR1-deficient mice yield no nigral dopaminergic neuron loss, linked to the absence of astroglial proliferation.

KEYWORDS:

6-OHDA; Fractalkine (CX3CL1); Fractalkine receptor (CX3CR1); MPTP; Neurodegeneration; Neuroinflammation; Parkinson’s disease

PMID:
26403659
DOI:
10.1007/s12640-015-9557-5
[Indexed for MEDLINE]

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