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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2023

Open Access 01-12-2023 | Mood Disorders | Research

CD200 in dentate gyrus improves depressive-like behaviors of mice through enhancing hippocampal neurogenesis via alleviation of microglia hyperactivation

Authors: Xi Chen, Qian-Qian Cui, Xiao-Hai Hu, Jian Ye, Zi-Cun Liu, Yuan-Xi Mei, Fang Wang, Zhuang-Li Hu, Jian-Guo Chen

Published in: Journal of Neuroinflammation | Issue 1/2023

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Abstract

Background

Neuroinflammation and microglia play critical roles in the development of depression. Cluster of differentiation 200 (CD200) is an anti-inflammatory glycoprotein that is mainly expressed in neurons, and its receptor CD200R1 is primarily in microglia. Although the CD200–CD200R1 pathway is necessary for microglial activation, its role in the pathophysiology of depression remains unknown.

Methods

The chronic social defeat stress (CSDS) with behavioral tests were performed to investigate the effect of CD200 on the depressive-like behaviors. Viral vectors were used to overexpress or knockdown of CD200. The levels of CD200 and inflammatory cytokines were tested with molecular biological techniques. The status of microglia, the expression of BDNF and neurogenesis were detected with immunofluorescence imaging.

Results

We found that the expression of CD200 was decreased in the dentate gyrus (DG) region of mice experienced CSDS. Overexpression of CD200 alleviated the depressive-like behaviors of stressed mice and inhibition of CD200 facilitated the susceptibility to stress. When CD200R1 receptors on microglia were knocked down, CD200 was unable to exert its role in alleviating depressive-like behavior. Microglia in the DG brain region were morphologically activated after exposure to CSDS. In contrast, exogenous administration of CD200 inhibited microglia hyperactivation, alleviated neuroinflammatory response in hippocampus, and increased the expression of BDNF, which in turn ameliorated adult hippocampal neurogenesis impairment in the DG induced by CSDS.

Conclusions

Taken together, these results suggest that CD200-mediated alleviation of microglia hyperactivation contributes to the antidepressant effect of neurogenesis in dentate gyrus in mice.
Appendix
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Literature
1.
Cui QQ, Hu ZL, Hu YL, Chen X, Wang J, Mao L, et al. Hippocampal CD 39/ ENTPD 1 promotes mouse depression-like behavior through hydrolyzing extracellular ATP. EMBO Rep. 2020;21: e47857.PubMedPubMedCentralCrossRef
2.
Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16:472–86.PubMedCrossRef
3.
Seney ML, Glausier J, Sibille E. Large-scale transcriptomic studies provide insight into sex differences in depression. Biol Psychiatry. 2021;91:14–24.PubMedCrossRef
4.
Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, et al. Major depressive disorder. Nat Rev Dis Prim. 2016;2:16065.PubMedCrossRef
5.
6.
7.
8.
Latham RM, Kieling C, Arseneault L, Kohrt BA, Moffitt TE, Rasmussen LJH, et al. Longitudinal associations between adolescents’ individualised risk for depression and inflammation in a UK cohort study. Brain Behav Immun. 2022;101:78–83.PubMedPubMedCentralCrossRef
9.
Vogelzangs N, Duivis HE, Beekman ATF, Kluft C, Neuteboom J, Hoogendijk W, et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry. 2012;2: e79.PubMedPubMedCentralCrossRef
10.
Gaspersz R, Lamers F, Wittenberg G, Beekman ATF, Van Hemert AM, Schoevers RA, et al. The role of anxious distress in immune dysregulation in patients with major depressive disorder. Transl Psychiatry. 2017;7:1268.PubMedPubMedCentralCrossRef
11.
Benameur T, Soleti R, Porro C. The potential neuroprotective role of free and encapsulated quercetin mediated by miRNA against neurological diseases. Nutrients. 2021;13:1318.PubMedPubMedCentralCrossRef
12.
Zheng M, Li K, Chen T, Liu S, He L. Geniposide protects depression through BTK/JAK2/STAT1 signaling pathway in lipopolysaccharide-induced depressive mice. Brain Res Bull. 2021;170:65–73.PubMedCrossRef
13.
Ochocka N, Kaminska B. Microglia diversity in healthy and diseased brain: insights from single-cell omics. Int J Mol Sci. 2021;22:1–26.CrossRef
14.
Hill AS, Sahay A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology. 2015;40:2368–78.PubMedPubMedCentralCrossRef
15.
Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, et al. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry. 2014;19:699–709.PubMedCrossRef
16.
Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflamm. 2014;11:1–15.CrossRef
17.
Zhang J, Rong P, Zhang L, He H, Zhou T, Fan Y, et al. IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis. Sci Adv. 2021;7:eabb9888.PubMedPubMedCentralCrossRef
18.
Cox FF, Carney D, Miller AM, Lynch MA. CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav Immun. 2012;26:789–96.PubMedCrossRef
19.
Liu Y, Bando Y, Vargas-Lowy D, Elyaman W, Khoury SJ, Huang T, et al. CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis. J Neurosci. 2010;30:2025–38.PubMedPubMedCentralCrossRef
20.
Zhang S, Wang XJ, Tian LP, Pan J, Lu GQ, Zhang YJ, et al. CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson’s disease. J Neuroinflamm. 2011;8:154.CrossRef
21.
Shrivastava K, Gonzalez P, Acarin L. The immune inhibitory complex CD200/CD200R is developmentally regulated in the mouse brain. J Comp Neurol. 2012;520:2657–75.PubMedCrossRef
22.
Rabaneda-Lombarte N, Serratosa J, Bové J, Vila M, Saura J, Solà C. The CD200R1 microglial inhibitory receptor as a therapeutic target in the MPTP model of Parkinson’s disease. J Neuroinflamm. 2021;18:88.CrossRef
23.
Hatherley D, Barclay AN. The CD200 and CD200 receptor cell surface proteins interact through their N-terminal immunoglobulin-like domains. Eur J Immunol. 2004;34:1688–94.PubMedCrossRef
24.
Hoek RH, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290:1768–71.PubMedCrossRef
25.
Sun H, He X, Tao X, Hou T, Chen M, He M, et al. The CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity after stroke. J Neuroinflamm. 2020;17:171.CrossRef
26.
Jiang X, Yi S, Liu Q, Su D, Li L, Xiao C, et al. Asperosaponin VI ameliorates the CMS-induced depressive-like behaviors by inducing a neuroprotective microglial phenotype in hippocampus via PPAR-γ pathway. J Neuroinflamm. 2022;19:1–19.CrossRef
27.
28.
Varnum MM, Kiyota T, Ingraham KL, Ikezu S, Ikezu T. The anti-inflammatory glycoprotein, CD200, restores neurogenesis and enhances amyloid phagocytosis in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2015;36:2995–3007.PubMedPubMedCentralCrossRef
29.
Sun H, Li A, Hou T, Tao X, Chen M, Wu C, et al. Neurogenesis promoted by the CD200/CD200R signaling pathway following treadmill exercise enhances post-stroke functional recovery in rats. Brain Behav Immun. 2019;82:354–71.PubMedCrossRef
30.
Li MX, Zheng HL, Luo Y, He JG, Wang W, Han J, et al. Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs. Mol Psychiatry. 2018;23:556–68.PubMedCrossRef
31.
32.
Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212.PubMedCrossRef
33.
Walsh JJ, Friedman AK, Sun H, Heller EA, Ku SM, Juarez B, et al. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci. 2014;17:27–9.PubMedCrossRef
34.
Kim J, Kang S, Choi TY, Chang KA, Koo JW. Metabotropic glutamate receptor 5 in amygdala target neurons regulates susceptibility to chronic social stress. Biol Psychiatry. 2022;92:104–15.PubMedCrossRef
35.
Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature. 2012;487:183–9.PubMedPubMedCentralCrossRef
36.
He JG, Zhou HY, Xue SG, Lu JJ, Xu JF, Zhou B, et al. Transcription factor TWIST1 integrates dendritic remodeling and chronic stress to promote depressive-like behaviors. Biol Psychiatry. 2021;89:615–26.PubMedCrossRef
37.
Xie WL, Zheng HL, Li HH, Lu JJ, Xue SG, Luo Y, et al. Deficiency of glycosylated α-dystroglycan in ventral hippocampus bridges the destabilization of gamma-aminobutyric acid type A receptors with the depressive-like behaviors of male mice. Biol Psychiatry. 2021;91:593–603.PubMedCrossRef
38.
Hernangómez M, Klusáková I, Joukal M, Hradilová-Svíženská I, Guaza C, Dubovỳ P. CD200R1 agonist attenuates glial activation, inflammatory reactions, and hypersensitivity immediately after its intrathecal application in a rat neuropathic pain model. J Neuroinflamm. 2016;13:43.CrossRef
39.
Anacker C, Luna VM, Stevens GS, Millette A, Shores R, Jimenez JC, et al. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature. 2018;559:98–102.PubMedPubMedCentralCrossRef
40.
Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.PubMedCrossRef
41.
Chamera K, Kotarska K, Szuster-Głuszczak M, Trojan E, Skórkowska A, Pomierny B, et al. The prenatal challenge with lipopolysaccharide and polyinosinic: polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours. J Neuroinflamm. 2020;17:247.CrossRef
42.
Wasko NJ, Kulak MH, Paul D, Nicaise AM, Yeung ST, Nichols FC, et al. Systemic TLR2 tolerance enhances central nervous system remyelination. J Neuroinflamm. 2019;16(1):158.CrossRef
43.
Kobashi S, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, et al. Transplantation of M2-deviated microglia promotes recovery of motor function after spinal cord injury in mice. Mol Ther. 2020;28:254–65.PubMedCrossRef
44.
Ferreira AC, Santos T, Sampaio-Marques B, Novais A, Mesquita SD, Ludovico P, et al. Lipocalin-2 regulates adult neurogenesis and contextual discriminative behaviours. Mol Psychiatry. 2018;23:1031–9.PubMedCrossRef
45.
Kim EJ, Leung CT, Reed RR, Johnson JE. In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis. J Neurosci. 2007;27:12764–74.PubMedPubMedCentralCrossRef
46.
Putatunda R, Ho WZ, Hu W. HIV-1 and compromised adult neurogenesis: emerging evidence for a new paradigm of HAND persistence. AIDS Rev. 2019;21:11–22.PubMedPubMedCentralCrossRef
47.
López-Juárez A, Howard J, Ullom K, Howard L, Grande A, Pardo A, et al. Gsx2 controls region-specific activation of neural stem cells and injury-induced neurogenesis in the adult subventricular zone. Genes Dev. 2013;27:1272.PubMedPubMedCentralCrossRef
48.
Ge F, Yang H, Lu W, Shi H, Chen Q, Luo Y, et al. Ovariectomy induces microglial cell activation and inflammatory response in rat prefrontal cortices to accelerate the chronic unpredictable stress-mediated anxiety and depression. Biomed Res Int. 2020;2020:3609758.PubMedPubMedCentralCrossRef
49.
Koning N, Swaab DF, Hoek RM, Huitinga I. Distribution of the immune inhibitory molecules CD200 and CD200R in the normal central nervous system and multiple sclerosis lesions suggests neuron-glia and glia-glia interactions. J Neuropathol Exp Neurol. 2009;68:159–67.PubMedCrossRef
50.
Walker DG, Dalsing-Hernandez JE, Campbell NA, Lue LF. Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: a potential mechanism leading to chronic inflammation. Exp Neurol. 2009;215:5.PubMedCrossRef
51.
Luo XG, Zhang JJ, Zhang CD, Liu R, Zheng L, Wang XJ, et al. Altered regulation of CD200 receptor in monocyte-derived macrophages from individuals with Parkinson’s disease. Neurochem Res. 2010;35:540–7.PubMedCrossRef
52.
Frank MG, Fonken LK, Annis JL, Watkins LR, Maier SF. Stress disinhibits microglia via down-regulation of CD200R: a mechanism of neuroinflammatory priming. Brain Behav Immun. 2018;69:62.PubMedCrossRef
53.
Frank MG, Annis JL, Watkins LR, Maier SF. Glucocorticoids mediate stress induction of the alarmin HMGB1 and reduction of the microglia checkpoint receptor CD200R1 in limbic brain structures. Brain Behav Immun. 2019;80:678–87.PubMedPubMedCentralCrossRef
54.
Wang HT, Huang FL, Hu ZL, Zhang WJ, Qiao XQ, Huang YQ, et al. Early-life social isolation-induced depressive-like behavior in rats results in microglial activation and neuronal histone methylation that are mitigated by minocycline. Neurotox Res. 2017;31:505–20.PubMedCrossRef
55.
Helmut K, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461–553.CrossRef
56.
57.
Wang H, He Y, Sun Z, Ren S, Liu M, Wang G, et al. Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression. J Neuroinflamm. 2022;19:132.CrossRef
58.
Waisman A, Liblau RS, Becher B. Innate and adaptive immune responses in the CNS. Lancet Neurol. 2015;14:945–55.PubMedCrossRef
59.
Nie X, Kitaoka S, Tanaka K, Segi-Nishida E, Imoto Y, Ogawa A, et al. The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation. Neuron. 2018;99:464-479.e7.PubMedCrossRef
60.
Zhang Y, Du L, Bai Y, Han B, He C, Gong L, et al. CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination. Mol Psychiatry. 2020;25:1175–90.PubMedCrossRef
61.
Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49.PubMedCrossRef
62.
Yirmiya R, Rimmerman N, Reshef R. Depression as a microglial disease. Trends Neurosci. 2015;38:637–58.PubMedCrossRef
63.
Santos LE, Beckman D, Ferreira ST. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav Immun. 2016;55:151–65.PubMedCrossRef
64.
Javanmehr N, Saleki K, Alijanizadeh P, Rezaei N. Microglia dynamics in aging-related neurobehavioral and neuroinflammatory diseases. J Neuroinflamm. 2022;19:1–20.CrossRef
65.
Miller AD, Westmoreland SV, Evangelous NR, Graham A, Sledge J, Nesathurai S. Acute traumatic spinal cord injury induces glial activation in the cynomolgus macaque (Macaca fascicularis). J Med Primatol. 2012;41:202.PubMedPubMedCentralCrossRef
66.
Ju F, Ran Y, Zhu L, Cheng X, Gao H, Xi X, et al. Increased BBB permeability enhances activation of microglia and exacerbates loss of dendritic spines after transient global cerebral ischemia. Front Cell Neurosci. 2018;12:236.PubMedPubMedCentralCrossRef
67.
Takata F, Nakagawa S, Matsumoto J, Dohgu S. Blood–brain barrier dysfunction amplifies the development of neuroinflammation: understanding of cellular events in brain microvascular endothelial cells for prevention and treatment of BBB dysfunction. Front Cell Neurosci. 2021;15: 661838.PubMedPubMedCentralCrossRef
68.
Le CS, Di HX, Li JW, Zhong JW, Lin HR, Zhou YT, et al. CD200Fc improves neurological function by protecting the blood–brain barrier after intracerebral hemorrhage. Cell Transplant. 2019;28:1321–8.PubMedPubMedCentralCrossRef
69.
70.
Sierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7:483–95.PubMedPubMedCentralCrossRef
Metadata
Title
CD200 in dentate gyrus improves depressive-like behaviors of mice through enhancing hippocampal neurogenesis via alleviation of microglia hyperactivation
Authors
Xi Chen
Qian-Qian Cui
Xiao-Hai Hu
Jian Ye
Zi-Cun Liu
Yuan-Xi Mei
Fang Wang
Zhuang-Li Hu
Jian-Guo Chen
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-023-02836-4

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