title: Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation.
abstract: The immunosuppressive nature of glucocorticoids has been well documented both in vitro and in vivo. This glucocorticoid-mediated immunosuppression has also been observed in immune cells within the central nervous system (CNS). For example, microglia have previously been shown to exhibit decreased proliferation, cytokine production, and antigen presentation upon treatment with glucocorticoids in vitro. Despite these in vitro findings, the impact of glucocorticoids on microglia function in vivo has not been fully investigated. To determine the interaction between glucocorticoids and microglia within the CNS, we used a restraint model of psychological stress to elevate corticosterone levels in mice. Quantification of microglia from stressed mice indicated that four sessions of stress induced the proliferation of microglia. This proliferation was a function of corticosterone-induced activation of the N-methyl-D-aspartate (NMDA) receptor within the CNS since blockade of corticosterone synthesis, the glucocorticoid receptor, or the NMDA receptor each prevented stress-induced increases in microglia number. In addition, the NMDA receptor antagonist MK-801 prevented increases in microglia following exogenous corticosterone administration to non-stressed mice. We conclude that activation of the NMDA receptor and subsequent microglia proliferation is a downstream effect of elevated corticosterone levels. These findings demonstrate that elevated levels of glucocorticoids are able to activate microglia in vivo and suggest that stress is able to induce a pro-inflammatory response within the CNS. A pro-inflammatory microglia response may be a contributing factor in the development of various stress-induced inflammatory conditions in the CNS.
authors.affiliation: Graduate Program in Neuroscience, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
authors.forename: Aji
authors.initials: A
authors.lastname: Nair
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bonneau
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D003345:Corticosterone / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004326:Drinking / Q000187:drug effects; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D005938:Glucocorticoids / Q000097:blood*; D006727:Hormone Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D015735:Mifepristone / Q000494:pharmacology; D008954:Models, Biological; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011863:Radioimmunoassay / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012149:Restraint, Physical / Q000379:methods; D013312:Stress, Physiological / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000943:Antigens, Differentiation; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005938:Glucocorticoids; D006727:Hormone Antagonists; D018809:Proliferating Cell Nuclear Antigen; D016194:Receptors, N-Methyl-D-Aspartate; C036763:monocyte-macrophage differentiation antigen; D015735:Mifepristone; D016291:Dizocilpine Maleate; D003345:Corticosterone; D008797:Metyrapone