Knockout of CXCR5 increases the population of immature neural cells and decreases proliferation in the hippocampal dentate gyrus

Journal of Neuroinflammation

Bernhard T Baune²  Frances Corrigan³  Michael J Stuart¹ 

[1] School of Medicine, James Cook University, Townsville QLD 4811, Australia;Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide SA 5005, Australia;Discipline of Psychiatry, University of Adelaide, Adelaide SA 5005, Australia

关键词: Cognition;    Depression;    Hippocampus;    Progenitor cell;    Stem cell;    Proliferation;    Chemokine;    CXCL13;    CXCR5;   

Others  :  812707
DOI  :  10.1186/1742-2094-11-31

 received in 2013-10-09, accepted in 2014-02-02,  发布年份 2014

【 摘 要 】

Background

The process of neurogenesis in which new neurons are generated by proliferation and differentiation of neural stem/progenitor cells (NSCs/NPCs) has been a topic of intensive recent investigation. Investigations of the factors which regulate this process have recently begun to include immune factors including immune cells and cytokines, however the class of immune proteins designated as chemokines have been relatively neglected. Increasing evidence for novel brain-specific mechanisms of chemokines beyond their classical chemotactic functions has suggested that they may play a role in the regulation of NSC/NPC biology.

Methods

We have investigated the role of the chemokine receptor CXCR5 (ligand is CXCL13) in the activity of these cells through neurobiological and behavioural analysis of CXCR5-deficient mice (CXCR5^-/-). These investigations included: immunohistochemistry for the markers Ki67, nestin, doublecortin, and IBA-1, neurosphere assays, and the baseline behavioural tests: open field test and sucrose preference test.

Results

We observed a significant increase in doublecortin and nestin staining in the hippocampal dentate gyrus (P = 0.02 and P = 0.0008, respectively) of CXCR5^-/- animals as compared to wild-type controls. This was accompanied by a decrease in Ki67 staining subgranular zone (P = 0.009). Behavioural correlates included a significant increase in baseline locomotor activity in an open field test (P <0.00018) and a decrease in stress reactivity in that test (P = 0.015). Deficiency in CXCR5 was not associated with alterations in hippocampal microglial density, microglial activation or systemic cytokine levels, nor with loss of NSC/NPC populations in the neurosphere assay.

Conclusions

These findings are the first to describe a brain-specific function of CXCR5 under physiological conditions. CXCR5 reduces maintenance of immature neural cell populations and enhances proliferation of subgranular zone cells in the hippocampal dentate gyrus, however the mechanism of these effects remains unclear. Further research into the regulation of NSC/NPC activity should consider investigation of CXCR5 and other chemokines which may be relevant to the pathophysiology of psychiatric disorders including depression, anxiety and cognitive impairment/dementia.

【 授权许可】

   
2014 Stuart et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH: Neurogenesis in the adult human hippocampus. Nat Med 1998, 4:1313-1317.
• [2]Neves G, Cooke SF, Bliss TV: Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci 2008, 9:65-75.
• [3]McAfoose J, Baune BT: Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 2009, 33:355-366.
• [4]Eyre H, Baune BT: Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 2012, 37:1397-1416.
• [5]Eisch AJ, Petrik D: Depression and hippocampal neurogenesis: a road to remission? Science 2012, 338:72-75.
• [6]Pencea V, Bingaman KD, Wiegand SJ, Luskin MB: Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 2001, 21:6706-6717.
• [7]Jhaveri DJ, Mackay EW, Hamlin AS, Marathe SV, Nandam LS, Vaidya VA, Bartlett PF: Norepinephrine directly activates adult hippocampal precursors via beta3-adrenergic receptors. J Neurosci 2010, 30:2795-2806.
• [8]Martino G, Pluchino S, Bonfanti L, Schwartz M: Brain regeneration in physiology and pathology: the immune signature driving therapeutic plasticity of neural stem cells. Physiol Rev 2011, 91:1281-1304.
• [9]Kokaia Z, Martino G, Schwartz M, Lindvall O: Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat Neurosci 2012, 15:1078-1087.
• [10]Li L, Walker TL, Zhang Y, Mackay EW, Bartlett PF: Endogenous interferon gamma directly regulates neural precursors in the non-inflammatory brain. J Neurosci 2010, 30:9038-9050.
• [11]Rostene W, Kitabgi P, Parsadaniantz SM: Chemokines: a new class of neuromodulator? Nat Rev Neurosci 2007, 8:895-903.
• [12]Reaux-Le Goazigo A, Van Steenwinckel J, Rostene W, Melik Parsadaniantz S: Current status of chemokines in the adult CNS. Prog Neurobiol 2013, 104:67-92.
• [13]Vukovic J, Colditz MJ, Blackmore DG, Ruitenberg MJ, Bartlett PF: Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J Neurosci 2012, 32:6435-6443.
• [14]Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M: A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 1996, 87:1037-1047.
• [15]Rainey-Barger EK, Rumble JM, Lalor SJ, Esen N, Segal BM, Irani DN: The lymphoid chemokine, CXCL13, is dispensable for the initial recruitment of B cells to the acutely inflamed central nervous system. Brain Behav Immun 2011, 25:922-931.
• [16]Moylan S, Eyre HA, Maes M, Baune BT, Jacka FN, Berk M: Exercising the worry away: how inflammation, oxidative and nitrogen stress mediates the beneficial effect of physical activity on anxiety disorder symptoms and behaviours. Neurosci Biobehav Rev 2013, 37:573-584.
• [17]Moylan S, Maes M, Wray NR, Berk M: The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry 2013, 18:595-606.
• [18]Flynn G, Maru S, Loughlin J, Romero IA, Male D: Regulation of chemokine receptor expression in human microglia and astrocytes. J Neuroimmunol 2003, 136:84-93.
• [19]Weiss N, Deboux C, Chaverot N, Miller F, Baron-Van Evercooren A, Couraud PO, Cazaubon S: IL8 and CXCL13 are potent chemokines for the recruitment of human neural precursor cells across brain endothelial cells. J Neuroimmunol 2010, 223:131-134.
• [20]Kizil C, Dudczig S, Kyritsis N, Machate A, Blaesche J, Kroehne V, Brand M: The chemokine receptor cxcr5 regulates the regenerative neurogenesis response in the adult zebrafish brain. Neural Dev 2012, 7:27. BioMed Central Full Text
• [21]Walker TL, White A, Black DM, Wallace RH, Sah P, Bartlett PF: Latent stem and progenitor cells in the hippocampus are activated by neural excitation. J Neurosci 2008, 28:5240-5247.
• [22]Bull ND, Bartlett PF: The adult mouse hippocampal progenitor is neurogenic but not a stem cell. J Neurosci 2005, 25:10815-10821.
• [23]Baune BT, Wiede F, Braun A, Golledge J, Arolt V, Koerner H: Cognitive dysfunction in mice deficient for TNF- and its receptors. Am J Med Genet B Neuropsychiatr Genet 2008, 147B:1056-1064.
• [24]Hart PC, Bergner CL, Smolinsky AN, Dufour BD, Egan RJ, Laporte JL, Kalueff AV: Experimental models of anxiety for drug discovery and brain research. Methods Mol Biol 2010, 602:299-321.
• [25]Lawson MA, Kelley KW, Dantzer R: Intracerebroventricular administration of HIV-1 Tat induces brain cytokine and indoleamine 2,3-dioxygenase expression: a possible mechanism for AIDS comorbid depression. Brain Behav Immun 2011, 25:1569-1575.
• [26]Park SE, Lawson M, Dantzer R, Kelley KW, McCusker RH: Insulin-like growth factor-I peptides act centrally to decrease depression-like behavior of mice treated intraperitoneally with lipopolysaccharide. J Neuroinflammation 2011, 8:179. BioMed Central Full Text
• [27]Rao MS, Hattiangady B, Shetty AK: The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus. Aging Cell 2006, 5:545-558.
• [28]Beynon SB, Walker FR: Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. Neuroscience 2012, 225:162-171.
• [29]Sousa N, Almeida OF, Wotjak CT: A hitchhiker’s guide to behavioral analysis in laboratory rodents. Genes Brain Behav 2006, Suppl 2:5-24.
• [30]Garthe A, Kempermann G: An old test for new neurons: refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis. Front Neurosci 2013, 7:63.
• [31]Overstreet DH: Modeling depression in animal models. Methods Mol Biol 2012, 829:125-144.
• [32]Bartko SJ, Romberg C, White B, Wess J, Bussey TJ, Saksida LM: Intact attentional processing but abnormal responding in M1 muscarinic receptor-deficient mice using an automated touchscreen method. Neuropharmacology 2011, 61:1366-1378.
• [33]Kameda M, Taylor CJ, Walker TL, Black DM, Abraham WC, Bartlett PF: Activation of latent precursors in the hippocampus is dependent on long-term potentiation. Transl Psychiatry 2012, 2:e72.
• [34]Petrik D, Lagace DC, Eisch AJ: The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 2012, 62:21-34.
• [35]Baune BT, Smith E, Reppermund S, Air T, Samaras K, Lux O, Brodaty H, Sachdev P, Trollor JN: Inflammatory biomarkers predict depressive, but not anxiety symptoms during aging: the prospective Sydney Memory and Aging Study. Psychoneuroendocrinology 2012, 37:1521-1530.
• [36]Grassi-Oliveira R, Brieztke E, Teixeira A, Pezzi JC, Zanini M, Lopes RP, Bauer ME: Peripheral chemokine levels in women with recurrent major depression with suicidal ideation. Rev Bras Psiquiatr 2012, 34:71-75.