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

Stuart MJ, Corrigan F, Baune BT - J Neuroinflammation (2014)

Bottom Line: 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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Discipline of Psychiatry, University of Adelaide, Adelaide SA 5005, Australia. bernhard.baune@adelaide.edu.au.

ABSTRACT

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.

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CXCR5-/- is associated with increased baseline locomotor activity and decreased anxiety-like behaviour but not anhedonia-like behaviour. (A) CXCR5-/- is associated with increased locomotor activity over 5 min in the open field test as compared to WT controls (* P <0.0001; n = 11 per group). (B) CXCR5-/- is associated with increased time spent in the inner zone of the open field test as compared to WT controls (* P = 0.015; n = 11 per group). (C) No difference in saccharin preference between CXCR5-/- and WT animals (P = 0.098; n = 11 per group).
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Figure 4: CXCR5-/- is associated with increased baseline locomotor activity and decreased anxiety-like behaviour but not anhedonia-like behaviour. (A) CXCR5-/- is associated with increased locomotor activity over 5 min in the open field test as compared to WT controls (* P <0.0001; n = 11 per group). (B) CXCR5-/- is associated with increased time spent in the inner zone of the open field test as compared to WT controls (* P = 0.015; n = 11 per group). (C) No difference in saccharin preference between CXCR5-/- and WT animals (P = 0.098; n = 11 per group).

Mentions: We next aimed to investigate the behavioural consequences of CXCR5 deficiency. A useful initial test is the open field test which provides information on baseline locomotor activity which may be a significant confounder for further behavioural testing[29]. In our study we found that CXCR5 deficiency was associated with a two-fold increase in baseline locomotor activity as assessed by distance travelled during the test (21.9 ± 0.6 vs. 13.0 ± 0.9; n = 11 per group; P <0.0001) (Figure 4). We also found an increase in time spent in the inner two thirds of the open field by CXCR5 deficient animals which may be interpreted as a reduction in stress responsiveness (55.9 ± 6.2 vs. 34.1 ± 5.4; n = 11 per group; P = 0.015), however such an interpretation should be regarded with caution given the overall increase in locomotor activity (Figure 4A, B). In view of the result on locomotor activity which would make it difficult to interpret the results of conventional hippocampus-dependent learning and memory tasks (for example, Barnes Maze or Morris Water Maze[30]), we have pursued behavioural testing which did not require locomotor activity.


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

Stuart MJ, Corrigan F, Baune BT - J Neuroinflammation (2014)

CXCR5-/- is associated with increased baseline locomotor activity and decreased anxiety-like behaviour but not anhedonia-like behaviour. (A) CXCR5-/- is associated with increased locomotor activity over 5 min in the open field test as compared to WT controls (* P <0.0001; n = 11 per group). (B) CXCR5-/- is associated with increased time spent in the inner zone of the open field test as compared to WT controls (* P = 0.015; n = 11 per group). (C) No difference in saccharin preference between CXCR5-/- and WT animals (P = 0.098; n = 11 per group).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3928586&req=5

Figure 4: CXCR5-/- is associated with increased baseline locomotor activity and decreased anxiety-like behaviour but not anhedonia-like behaviour. (A) CXCR5-/- is associated with increased locomotor activity over 5 min in the open field test as compared to WT controls (* P <0.0001; n = 11 per group). (B) CXCR5-/- is associated with increased time spent in the inner zone of the open field test as compared to WT controls (* P = 0.015; n = 11 per group). (C) No difference in saccharin preference between CXCR5-/- and WT animals (P = 0.098; n = 11 per group).
Mentions: We next aimed to investigate the behavioural consequences of CXCR5 deficiency. A useful initial test is the open field test which provides information on baseline locomotor activity which may be a significant confounder for further behavioural testing[29]. In our study we found that CXCR5 deficiency was associated with a two-fold increase in baseline locomotor activity as assessed by distance travelled during the test (21.9 ± 0.6 vs. 13.0 ± 0.9; n = 11 per group; P <0.0001) (Figure 4). We also found an increase in time spent in the inner two thirds of the open field by CXCR5 deficient animals which may be interpreted as a reduction in stress responsiveness (55.9 ± 6.2 vs. 34.1 ± 5.4; n = 11 per group; P = 0.015), however such an interpretation should be regarded with caution given the overall increase in locomotor activity (Figure 4A, B). In view of the result on locomotor activity which would make it difficult to interpret the results of conventional hippocampus-dependent learning and memory tasks (for example, Barnes Maze or Morris Water Maze[30]), we have pursued behavioural testing which did not require locomotor activity.

Bottom Line: 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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Discipline of Psychiatry, University of Adelaide, Adelaide SA 5005, Australia. bernhard.baune@adelaide.edu.au.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus