title: CX3CR1 Disruption Differentially Influences Dopaminergic Neuron Degeneration in Parkinsonian Mice Depending on the Neurotoxin and Route of Administration.
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.
authors.affiliation: 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.|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.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Preto, Brazil.
authors.forename: Fabrine Sales Massafera
authors.initials: FS
authors.lastname: Tristão
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Márcio
authors.initials: M
authors.lastname: Lazzarini
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Martin
authors.affiliation: 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.
authors.forename: Majid
authors.initials: M
authors.lastname: Amar
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Stühmer
authors.affiliation: Department of Molecular Physiology, University of Saarland, Homburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Lucas Araújo Caldi
authors.initials: LA
authors.lastname: Gomes
authors.affiliation: INSERM UMR S894, Université Pierre et Marie Curie, UPMC, Paris, France.
authors.forename: Laurance
authors.initials: L
authors.lastname: Lanfumey
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Campus Trindade, Florianópolis, SC, Brazil.
authors.forename: Rui D
authors.initials: RD
authors.lastname: Prediger
authors.affiliation: 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.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Sepulveda
authors.affiliation: 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.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Preto, Brazil. eadelbel@forp.usp.br.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Del-Bel
authors.affiliation: 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.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D016627:Oxidopamine; D004298:Dopamine
keywords: 6-OHDA; Fractalkine (CX3CL1); Fractalkine receptor (CX3CR1); MPTP; Neurodegeneration; Neuroinflammation; Parkinson’s disease