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

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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.

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Acknowledgments

The authors acknowledge Sabine Stolpe and Tanja Nilsson for their technical support. The authors gratefully thank the financial support and grants provided by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), CAPES-COFECUB (France/Brazil; 681/2010), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Programa Ciência sem Fronteiras (CsF, Brazil), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Brazil), German Academic Exchange Service DAAD-ProBral/CAPES (FK/EADB) and the Max Planck Society (WS). SM was funded through the Cluster of Excellence and DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain.

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Authors and Affiliations

  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

    Fabrine Sales Massafera Tristão, Majid Amar, Julia E. Sepulveda & Rita Raisman-Vozari

  2. Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    Márcio Lazzarini, Sabine Martin, Walter Stühmer & Lucas Araújo Caldi Gomes

  3. Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany

    Sabine Martin & Walter Stühmer

  4. Department of Molecular Physiology, University of Saarland, Homburg, Germany

    Frank Kirchhoff

  5. INSERM UMR S894, Université Pierre et Marie Curie, UPMC, Paris, France

    Laurance Lanfumey

  6. Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Campus Trindade, Florianópolis, SC, Brazil

    Rui D. Prediger

  7. 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

    Fabrine Sales Massafera Tristão & Elaine A. Del-Bel

  8. Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Preto, Brazil

    Fabrine Sales Massafera Tristão & Elaine A. Del-Bel

Authors
  1. Fabrine Sales Massafera Tristão
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  2. Márcio Lazzarini
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  3. Sabine Martin
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  4. Majid Amar
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  5. Walter Stühmer
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  6. Frank Kirchhoff
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  7. Lucas Araújo Caldi Gomes
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  8. Laurance Lanfumey
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  9. Rui D. Prediger
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  10. Julia E. Sepulveda
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  11. Elaine A. Del-Bel
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  12. Rita Raisman-Vozari
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Corresponding authors

Correspondence to Elaine A. Del-Bel or Rita Raisman-Vozari.

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Conflict of interest

The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no financial or personal conflicts of interest related to this study.

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Tristão, F.S.M., Lazzarini, M., Martin, S. et al. CX3CR1 Disruption Differentially Influences Dopaminergic Neuron Degeneration in Parkinsonian Mice Depending on the Neurotoxin and Route of Administration. Neurotox Res 29, 364–380 (2016). https://doi.org/10.1007/s12640-015-9557-5

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  • DOI: https://doi.org/10.1007/s12640-015-9557-5

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