Antagonism of the brain P2X7 ion channel attenuates repeated social defeat induced microglia reactivity, monocyte recruitment and anxiety-like behavior in male mice.

Autor: Biltz RG; Department of Neuroscience, The Ohio State University, Wexner Medical Center, United States., Swanson SP; Department of Neuroscience, The Ohio State University, Wexner Medical Center, United States., Draime N; Department of Neuroscience, The Ohio State University, Wexner Medical Center, United States., Davis AC; Department of Neuroscience, The Ohio State University, Wexner Medical Center, United States., Yin W; Department of Neuroscience, The Ohio State University, Wexner Medical Center, United States., Goodman EJ; Department of Neuroscience, The Ohio State University, Wexner Medical Center, United States., Gallagher NR; Division of Biosciences, The Ohio State University College of Dentistry, United States; Institute for Behavioral Medicine Research, The Ohio State University, Wexner Medical Center, United States., Bhattacharya A; Neuroscience, Janssen Research and Development, LLC, San Diego, CA, United States., Sheridan JF; Department of Neuroscience, The Ohio State University, Wexner Medical Center, United States; Division of Biosciences, The Ohio State University College of Dentistry, United States; Chronic Brain Injury Program, The Ohio State University, United States; Institute for Behavioral Medicine Research, The Ohio State University, Wexner Medical Center, United States. Electronic address: John.Sheridan@osumc.edu., Godbout JP; Department of Neuroscience, The Ohio State University, Wexner Medical Center, United States; Chronic Brain Injury Program, The Ohio State University, United States; Institute for Behavioral Medicine Research, The Ohio State University, Wexner Medical Center, United States. Electronic address: Jonathan.Godbout@osumc.edu.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2024 Jan; Vol. 115, pp. 356-373. Date of Electronic Publication: 2023 Oct 31.
DOI: 10.1016/j.bbi.2023.10.011
Abstrakt: Chronic stress is linked to increased anxiety. Repeated social defeat (RSD) in mice causes anxiety that is dependent on activated neurons, reactive microglia, and accumulation of monocytes in the brain. This response requires interactions between the immune system and central nervous system (CNS). Neuronal activation within threat appraisal regions is a key response to RSD, however, it is unclear how microglia become activated. One potential explanation is that microglia express a purinergic non-selective ligand gated adenosine-triphosphate (ATP) receptor 7 (P2X7). Activation of P2X7 promotes the release of chemokines and cytokines, and recruitment of monocytes to the brain. Thus, the purpose of this study was to determine if a novel P2X7 antagonist blocked neuronal and microglia interactions and the corresponding anxiety following RSD. Male mice were administered (i.p.) a P2X7 antagonist, JNJ-54471300, prior to each cycle of RSD. Fourteen hours after RSD, behavioral deficits including social avoidance and anxiety-like were determined. Moreover, several immune parameters were assessed. RSD caused neuronal activation in stress-responsive regions, monocyte production and release, splenomegaly, and social avoidance. These parameters were unaffected by P2X7 antagonism. RSD-associated proportional area of Iba-1+ microglia, monocyte accumulation in the brain, IL-1β mRNA expression in enriched myeloid cells, plasma IL-6, and anxiety-like behavior were ameliorated by P2X7 antagonism. Gene expression analysis in the hippocampus and amygdala showed regional specific responses to RSD and some were reversed with P2X7 antagonism. Overall, blocking P2X7 activation attenuated RSD-induced microglia reactivity with corresponding reduction in neuroinflammation, monocyte accumulation, and anxiety-like behavior in male mice.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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