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Sustained Immunosuppression Alters Olfactory Function in the MRL Model of CNS Lupus

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Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is frequently accompanied by diverse neuropsychiatric manifestations. An increased frequency of olfactory deficits has been recently reported as another marker of CNS involvement in SLE patients. Similarly, we observed that spontaneous development of lupus-like disease in MRL/lpr mice is accompanied by altered olfaction-related behaviors. However, it remained unclear whether the behavioral deficits are due to systemic autoimmunity, or the distinct genetic make-up. To address this question, we presently examine whether prolonged treatment with the immunosuppressive drug cyclophosphamide (CY) restores odor-guided behaviors in MRL/lpr mice. Over 12 weekends, MRL/lpr and control MRL +/+ males were given ad lib access to a sweetened CY solution or a vehicle. Their responsiveness to different scents was assessed at ages corresponding to mild, modest, and severe disease. Odor-guided exploratory behavior was further examined in the novel object test at 21 weeks of age, shortly before terminal assessment of immunopathology. In comparison to control groups, MRL/lpr mice exposed to CY exhibited normal spleen size and antibody levels, as well as increased responsiveness to an attractant and a novel object. However, CY treatment also exacerbated their aberrant response to a repellent, suggesting a dual mode of action on brain olfactory systems. The present results reveal that generalized immunosuppression modulates odor-guided behaviors in lupus-prone animals. Although key pathogenic mechanisms are not clear, the findings strengthen the construct validity of the MRL model by supporting the hypothesis that onset of systemic autoimmunity alters the activity of olfactory circuits.

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Acknowledgements

We are thankful to Bhargav Thakar and Yitian Ma at EuroImmun Canada (Mississauga, ON) for assistance with behavioral scoring and ELISA assays, respectively. This study was supported by an Ontario Mental Health Foundation research grant to B. S as well as personal grants from The Father Sean O’Sullivan Research Foundation (St. Joseph’s Healthcare, Hamilton) and Ontario Graduate Scholarship to M.K.

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  1. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Psychology Building Rm. 303, 1280 Main St. West, Hamilton, ON, L8S 4K1, Canada

    Minesh Kapadia, Hui Zhao & Boris Sakic

  2. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

    Donglai Ma

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  1. Minesh Kapadia
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  2. Hui Zhao
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  3. Donglai Ma
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  4. Boris Sakic
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Correspondence to Boris Sakic.

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Kapadia, M., Zhao, H., Ma, D. et al. Sustained Immunosuppression Alters Olfactory Function in the MRL Model of CNS Lupus. J Neuroimmune Pharmacol 12, 555–564 (2017). https://doi.org/10.1007/s11481-017-9745-6

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  • DOI: https://doi.org/10.1007/s11481-017-9745-6

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