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Adenosine A2A receptor regulation of microglia morphological remodeling-gender bias in physiology and in a model of chronic anxiety

Molecular Psychiatry volume 22, pages 1035–1043 (2017)Cite this article

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Abstract

Developmental risk factors, such as the exposure to stress or high levels of glucocorticoids (GCs), may contribute to the pathogenesis of anxiety disorders. The immunomodulatory role of GCs and the immunological fingerprint found in animals prenatally exposed to GCs point towards an interplay between the immune and the nervous systems in the etiology of these disorders. Microglia are immune cells of the brain, responsive to GCs and morphologically altered in stress-related disorders. These cells are regulated by adenosine A2A receptors, which are also involved in the pathophysiology of anxiety. We now compare animal behavior and microglia morphology in males and females prenatally exposed to the GC dexamethasone. We report that prenatal exposure to dexamethasone is associated with a gender-specific remodeling of microglial cell processes in the prefrontal cortex: males show a hyper-ramification and increased length whereas females exhibit a decrease in the number and in the length of microglia processes. Microglial cells re-organization responded in a gender-specific manner to the chronic treatment with a selective adenosine A2A receptor antagonist, which was able to ameliorate microglial processes alterations and anxiety behavior in males, but not in females.

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References

  1. Drozdowicz LB, Bostwick JM . Psychiatric adverse effects of pediatric corticosteroid use. Mayo Clin Proc 2014; 89: 817–834.

    Article  CAS  Google Scholar 

  2. Khulan B, Drake AJ . Glucocorticoids as mediators of developmental programming effects. Best Pract Res Clin Endocrinol Metab 2012; 26: 689–700.

    Article  CAS  Google Scholar 

  3. Fukumoto K, Morita T, Mayanagi T, Tanokashira D, Yoshida T, Sakai A et al. Detrimental effects of glucocorticoids on neuronal migration during brain development. Mol Psychiatry 2009; 14: 1119–1131.

    Article  CAS  Google Scholar 

  4. Oliveira M, Rodrigues AJ, Leao P, Cardona D, Pego JM, Sousa N . The bed nucleus of stria terminalis and the amygdala as targets of antenatal glucocorticoids: implications for fear and anxiety responses. Psychopharmacology 2012; 220: 443–453.

    Article  CAS  Google Scholar 

  5. Tanokashira D, Morita T, Hayashi K, Mayanagi T, Fukumoto K, Kubota Y et al. Glucocorticoid suppresses dendritic spine development mediated by down-regulation of caldesmon expression. J Neurosci 2012; 32: 14583–14591.

    Article  CAS  Google Scholar 

  6. Crochemore C, Lu J, Wu Y, Liposits Z, Sousa N, Holsboer F et al. Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation. Mol Psychiatry 2005; 10: 790–798.

    Article  CAS  Google Scholar 

  7. Leao P, Sousa JC, Oliveira M, Silva R, Almeida OF, Sousa N . Programming effects of antenatal dexamethasone in the developing mesolimbic pathways. Synapse 2007; 61: 40–49.

    Article  CAS  Google Scholar 

  8. Li SX, Fujita Y, Zhang JC, Ren Q, Ishima T, Wu J et al. Role of the NMDA receptor in cognitive deficits, anxiety and depressive-like behavior in juvenile and adult mice after neonatal dexamethasone exposure. Neurobiol Dis 2014; 62: 124–134.

    Article  CAS  Google Scholar 

  9. Sousa N, Madeira MD, Paula-Barbosa MM . Effects of corticosterone treatment and rehabilitation on the hippocampal formation of neonatal and adult rats. An unbiased stereological study. Brain Res 1998; 794: 199–210.

    Article  CAS  Google Scholar 

  10. Sousa N, Almeida OF . Corticosteroids: sculptors of the hippocampal formation. Rev Neurosci 2002; 13: 59–84.

    Article  CAS  Google Scholar 

  11. Roque S, Oliveira TG, Nobrega C, Barreira-Silva P, Nunes-Alves C, Sousa N et al. Interplay between depressive-like behavior and the immune system in an animal model of prenatal dexamethasone administration. Front Behav Neurosci 2011; 5: 4.

    Article  PubMed Central  Google Scholar 

  12. Tanaka J, Fujita H, Matsuda S, Toku K, Sakanaka M, Maeda N . Glucocorticoid- and mineralocorticoid receptors in microglial cells: the two receptors mediate differential effects of corticosteroids. Glia 1997; 20: 23–37.

    Article  CAS  Google Scholar 

  13. Sierra A, Gottfried-Blackmore A, Milner TA, McEwen BS, Bulloch K . Steroid hormone receptor expression and function in microglia. Glia 2008; 56: 659–674.

    Article  Google Scholar 

  14. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P et al. Synaptic pruning by microglia is necessary for normal brain development. Science 2011; 333: 1456–1458.

    Article  CAS  Google Scholar 

  15. Cristovao G, Pinto MJ, Cunha RA, Almeida RD, Gomes CA . Activation of microglia bolsters synapse formation. Front Cell Neurosci 2014; 8: 153.

    Article  PubMed Central  Google Scholar 

  16. Ji K, Akgul G, Wollmuth LP, Tsirka SE . Microglia actively regulate the number of functional synapses. PloS One 2013; 8: e56293.

    Article  CAS  PubMed Central  Google Scholar 

  17. Lim SH, Park E, You B, Jung Y, Park AR, Park SG et al. Neuronal synapse formation induced by microglia and interleukin 10. PloS One 2013; 8: e81218.

    Article  PubMed Central  Google Scholar 

  18. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013; 155: 1596–1609.

    Article  CAS  PubMed Central  Google Scholar 

  19. Salter MW, Beggs S . Sublime microglia: expanding roles for the guardians of the CNS. Cell 2014; 158: 15–24.

    Article  CAS  Google Scholar 

  20. Kettenmann H, Kirchhoff F, Verkhratsky A . Microglia: new roles for the synaptic stripper. Neuron 2013; 77: 10–18.

    Article  CAS  Google Scholar 

  21. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neurosci 2005; 8: 752–758.

    Article  CAS  Google Scholar 

  22. Nimmerjahn A, Kirchhoff F, Helmchen F . Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314–1318.

    Article  CAS  Google Scholar 

  23. Hinwood M, Tynan RJ, Charnley JL, Beynon SB, Day TA, Walker FR . Chronic stress induced remodeling of the prefrontal cortex: structural re-organization of microglia and the inhibitory effect of minocycline. Cereb Cortex 2013; 23: 1784–1797.

    Article  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. Gyoneva S, Shapiro L, Lazo C, Garnier-Amblard E, Smith Y, Miller GW et al. Adenosine A2A receptor antagonism reverses inflammation-induced impairment of microglial process extension in a model of Parkinson's disease. Neurobiol Dis 2014; 67: 191–202.

    Article  CAS  PubMed Central  Google Scholar 

  26. Rial D, Lemos C, Pinheiro H, Duarte JM, Goncalves FQ, Real JI et al. Depression as a glial-based synaptic dysfunction. Front Cell Neurosci 2015; 9: 521.

    PubMed  Google Scholar 

  27. McKlveen JM, Myers B, Flak JN, Bundzikova J, Solomon MB, Seroogy KB et al. Role of prefrontal cortex glucocorticoid receptors in stress and emotion. Biol Psychiatry 2013; 74: 672–679.

    Article  CAS  PubMed Central  Google Scholar 

  28. Chattarji S, Tomar A, Suvrathan A, Ghosh S, Rahman MM . Neighborhood matters: divergent patterns of stress-induced plasticity across the brain. Nat Neurosci 2015; 18: 1364–1375.

    Article  CAS  Google Scholar 

  29. Calhoon GG, Tye KM . Resolving the neural circuits of anxiety. Nat Neurosci 2015; 18: 1394–1404.

    Article  CAS  Google Scholar 

  30. Gomes C, Ferreira R, George J, Sanches R, Rodrigues DI, Goncalves N et al. Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia. J Neuroinflammation 2013; 10: 16.

    Article  CAS  PubMed Central  Google Scholar 

  31. George J, Goncalves FQ, Cristovao G, Rodrigues L, Meyer Fernandes JR, Goncalves T et al. Different danger signals differently impact on microglial proliferation through alterations of ATP release and extracellular metabolism. Glia 2015; 63: 1636–1645.

    Article  Google Scholar 

  32. Orr AG, Orr AL, Li XJ, Gross RE, Traynelis SF . Adenosine A(2A) receptor mediates microglial process retraction. Nat Neurosci 2009; 12: 872–878.

    Article  CAS  PubMed Central  Google Scholar 

  33. Ardais AP, Borges MF, Rocha AS, Sallaberry C, Cunha RA, Porciuncula LO . Caffeine triggers behavioral and neurochemical alterations in adolescent rats. Neuroscience 2014; 270: 27–39.

    Article  CAS  Google Scholar 

  34. Batalha VL, Pego JM, Fontinha BM, Costenla AR, Valadas JS, Baqi Y et al. Adenosine A(2A) receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation. Mol Psychiatry 2013; 18: 320–331.

    Article  CAS  PubMed Central  Google Scholar 

  35. Cunha GM, Canas PM, Oliveira CR, Cunha RA . Increased density and synapto-protective effect of adenosine A2A receptors upon sub-chronic restraint stress. Neuroscience 2006; 141: 1775–1781.

    Article  CAS  Google Scholar 

  36. Gomes CV, Kaster MP, Tome AR, Agostinho PM, Cunha RA . Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 2011; 1808: 1380–1399.

    Article  CAS  Google Scholar 

  37. Kaster MP, Machado NJ, Silva HB, Nunes A, Ardais AP, Santana M et al. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proc Natl Acad Sci USA 2015; 112: 7833–7838.

    Article  CAS  Google Scholar 

  38. Wei CJ, Augusto E, Gomes CA, Singer P, Wang Y, Boison D et al. Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain. Biol Psychiatry 2014; 75: 855–863.

    Article  CAS  Google Scholar 

  39. Schwarz JM, Sholar PW, Bilbo SD . Sex differences in microglial colonization of the developing rat brain. J Neurochem 2012; 120: 948–963.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Oliveira M, Bessa JM, Mesquita A, Tavares H, Carvalho A, Silva R et al. Induction of a hyperanxious state by antenatal dexamethasone: a case for less detrimental natural corticosteroids. Biol Psychiatry 2006; 59: 844–852.

    Article  CAS  Google Scholar 

  41. Westwood FR . The female rat reproductive cycle: a practical histological guide to staging. Toxicol Pathol 2008; 36: 375–384.

    Article  Google Scholar 

  42. Chung S, Son GH, Kim K . Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. Biochim Biophys Acta 2011; 1812: 581–591.

    Article  CAS  Google Scholar 

  43. McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN et al. Mechanisms of stress in the brain. Nat Neurosci 2015; 18: 1353–1363.

    Article  CAS  PubMed Central  Google Scholar 

  44. Hodes GE, Kana V, Menard C, Merad M, Russo SJ . Neuroimmune mechanisms of depression. Nat Neurosci 2015; 18: 1386–1393.

    Article  CAS  PubMed Central  Google Scholar 

  45. Schafer DP, Lehrman EK, Stevens B . The ‘quad-partite’ synapse: microglia-synapse interactions in the developing and mature CNS. Glia 2013; 61: 24–36.

    Article  Google Scholar 

  46. Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B . Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol 2015; 36: 605–613.

    Article  PubMed Central  Google Scholar 

  47. Lenz KM, McCarthy MM . A starring role for microglia in brain sex differences. Neuroscientist 2015; 21: 306–321.

    Article  CAS  Google Scholar 

  48. Lenz KM, Nugent BM, Haliyur R, McCarthy MM . Microglia are essential to masculinization of brain and behavior. J Neurosci 2013; 33: 2761–2772.

    Article  CAS  PubMed Central  Google Scholar 

  49. Bollinger JL, Bergeon Burns CM, Wellman CL . Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. Brain Behav Immun 2016; 52: 88–97.

    Article  CAS  Google Scholar 

  50. Coelho JE, Alves P, Canas PM, Valadas JS, Shmidt T, Batalha VL et al. Overexpression of adenosine A2A receptors in rats: effects on depression, locomotion, and anxiety. Front Psychiatry 2014; 5: 67.

    Article  PubMed Central  Google Scholar 

  51. El Yacoubi M, Ledent C, Parmentier M, Bertorelli R, Ongini E, Costentin J et al. Adenosine A2A receptor antagonists are potential antidepressants: evidence based on pharmacology and A2A receptor knockout mice. Br J Pharmacol 2001; 134: 68–77.

    Article  CAS  Google Scholar 

  52. Dai SS, Zhou YG, Li W, An JH, Li P, Yang N et al. Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci 2010; 30: 5802–5810.

    Article  CAS  PubMed Central  Google Scholar 

  53. Rebola N, Simoes AP, Canas PM, Tome AR, Andrade GM, Barry CE et al. Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction. J Neurochem 2011; 117: 100–111.

    Article  CAS  Google Scholar 

  54. Mitrovic N, Gusevac I, Drakulic D, Stanojlovic M, Zlatkovic J, Sevigny J et al. Regional and sex-related differences in modulating effects of female sex steroids on ecto-5'-nucleotidase expression in the rat cerebral cortex and hippocampus. Gen Comp Endocrinol 2016; 235: 100–107.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by PEst-C/SAU/UI3282/2011-2013, POCI-01-0145-FEDER-007440 and UID/NEU/04539/2013 (FCT, Portugal, and COMPETE-FEDER). Catarina A. Gomes acknowledges a fellowship from Fundação para a Ciência e a Tecnologia, Portugal (SFRH/BPD/63013/2009. [Gomes] Filipa I. Baptista acknowledges a fellowship from Fundação para a Ciência e a Tecnologia, Portugal (SFRH/BPD/86830/2012).

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Author notes

  1. L Caetano and H Pinheiro: These authors contributed equally to this work.

  2. L Pinto and C A Gomes: These authors contributed equally to this work.

Authors and Affiliations

  1. CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    L Caetano, S G Ferreira, R A Cunha & C A Gomes

  2. Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    L Caetano, H Pinheiro, F I Baptista, S N Henriques, A F Ambrósio & C A Gomes

  3. CNC.IBILI Consortium, Coimbra, Portugal

    H Pinheiro, F I Baptista, S G Ferreira, A F Ambrósio, R A Cunha & C A Gomes

  4. Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal

    P Patrício, A Mateus-Pinheiro, N D Alves, B Coimbra, V M Sardinha, J F Oliveira, N Sousa, A J Rodrigues & L Pinto

  5. ICVS/3B’s-PT Government Associate Laboratory, Guimarães, Portugal

    P Patrício, A Mateus-Pinheiro, N D Alves, B Coimbra, C Cunha, A R Santos, V M Sardinha, J F Oliveira, N Sousa, A J Rodrigues & L Pinto

  6. Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    A F Ambrósio, R A Cunha & C A Gomes

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  1. L Caetano
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Correspondence to C A Gomes.

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Caetano, L., Pinheiro, H., Patrício, P. et al. Adenosine A2A receptor regulation of microglia morphological remodeling-gender bias in physiology and in a model of chronic anxiety. Mol Psychiatry 22, 1035–1043 (2017). https://doi.org/10.1038/mp.2016.173

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