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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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Effect of CXCR5 deficieny on neurogenesis in the adult dentate gyrus. (A) In CXCR5-/- animals the number of Ki67 positive cells was significantly reduced compared to WT controls (P = 0.009; n = 6 per group). (B) In CXCR5-/- animals the number of DCX positive cells was significantly increased compared to WT controls (P = 0.02; n = 6 per group). (C) In CXCR5-/- animals the number of Nestin positive cells was significantly increased compared to WT controls (P = 0.0008; n = 6 per group). Representative images of Ki67 (C, D), DCX (E, F) and Nestin (H, I) staining.
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Figure 1: Effect of CXCR5 deficieny on neurogenesis in the adult dentate gyrus. (A) In CXCR5-/- animals the number of Ki67 positive cells was significantly reduced compared to WT controls (P = 0.009; n = 6 per group). (B) In CXCR5-/- animals the number of DCX positive cells was significantly increased compared to WT controls (P = 0.02; n = 6 per group). (C) In CXCR5-/- animals the number of Nestin positive cells was significantly increased compared to WT controls (P = 0.0008; n = 6 per group). Representative images of Ki67 (C, D), DCX (E, F) and Nestin (H, I) staining.

Mentions: We investigated whether CXCR5 deficiency might impact upon hippocampal neurogenesis in 11-week-old (adult) mice. In order to assess this, we stained hippocampal sections for the proliferation marker Ki67, Nestin doublecortin (DCX), markers of immature neuronal cells. We counted only positive cells within the subgranular zone for Ki67. Within this subregion Ki67 positive cells are likely to represent proliferative activity of NPCs, and Nestin/DCX the immature cells of neuronal lineage which are generated by the differentiation and migration of those cells[27]. We found that CXCR5 deficiency was permissive of increased density of DCX positive cells in the granular and subgranular zones of the dentage gyrus (505 ± 19.2 vs. 420 ± 25.9; n = 6 per group; P = 0.02). A similar trend was observed in nestin positive cells (331 ± 8.2 vs. 280 ± 7; n = 6 per group; P = 0.0008) (Figure 1). This implies that CXCR5 signaling may impair the maintenance of these populations. Additionally, we demonstrated that CXCR5 deficiency suppressed the number of Ki67 positive cells in the subgranular zone as compared to WT controls (90.0 ± 6.3 vs. 116.3 ± 5.1; n = 6 per group; P = 0.009). This may represent indirect suppression of a compensatory mechanism which would act to maintain DCX and Nestin positive cells under physiological conditions, or a direct effect by which CXCR5 (known to be expressed on NSC/NPC[19]) would support proliferation of these cells. Taken together these data are most suggestive that CXCR5 may exert a detrimental effect on maintenance of Nestin and DCX positive cell populations - for example through a pro-apoptotic effect - requiring enhanced proliferation of subgranular zone cells to compensate. A further possibility is that CXCR5 may support differentiation further down a neuronal lineage, thereby 'draining’ the pools of DCX and Nestin positive cells and requiring an enhancement of subgranular zone cell proliferation (Ki67 positive) to replace the pool. An alternative explanation, in which CXCR5 impairs differentiation of proliferating cells into a neuronal lineage is less likely as this effect would not be expected to simultaneously enhance the proliferation of the subgranular zone precursor/stem cells.


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)

Effect of CXCR5 deficieny on neurogenesis in the adult dentate gyrus. (A) In CXCR5-/- animals the number of Ki67 positive cells was significantly reduced compared to WT controls (P = 0.009; n = 6 per group). (B) In CXCR5-/- animals the number of DCX positive cells was significantly increased compared to WT controls (P = 0.02; n = 6 per group). (C) In CXCR5-/- animals the number of Nestin positive cells was significantly increased compared to WT controls (P = 0.0008; n = 6 per group). Representative images of Ki67 (C, D), DCX (E, F) and Nestin (H, I) staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Effect of CXCR5 deficieny on neurogenesis in the adult dentate gyrus. (A) In CXCR5-/- animals the number of Ki67 positive cells was significantly reduced compared to WT controls (P = 0.009; n = 6 per group). (B) In CXCR5-/- animals the number of DCX positive cells was significantly increased compared to WT controls (P = 0.02; n = 6 per group). (C) In CXCR5-/- animals the number of Nestin positive cells was significantly increased compared to WT controls (P = 0.0008; n = 6 per group). Representative images of Ki67 (C, D), DCX (E, F) and Nestin (H, I) staining.
Mentions: We investigated whether CXCR5 deficiency might impact upon hippocampal neurogenesis in 11-week-old (adult) mice. In order to assess this, we stained hippocampal sections for the proliferation marker Ki67, Nestin doublecortin (DCX), markers of immature neuronal cells. We counted only positive cells within the subgranular zone for Ki67. Within this subregion Ki67 positive cells are likely to represent proliferative activity of NPCs, and Nestin/DCX the immature cells of neuronal lineage which are generated by the differentiation and migration of those cells[27]. We found that CXCR5 deficiency was permissive of increased density of DCX positive cells in the granular and subgranular zones of the dentage gyrus (505 ± 19.2 vs. 420 ± 25.9; n = 6 per group; P = 0.02). A similar trend was observed in nestin positive cells (331 ± 8.2 vs. 280 ± 7; n = 6 per group; P = 0.0008) (Figure 1). This implies that CXCR5 signaling may impair the maintenance of these populations. Additionally, we demonstrated that CXCR5 deficiency suppressed the number of Ki67 positive cells in the subgranular zone as compared to WT controls (90.0 ± 6.3 vs. 116.3 ± 5.1; n = 6 per group; P = 0.009). This may represent indirect suppression of a compensatory mechanism which would act to maintain DCX and Nestin positive cells under physiological conditions, or a direct effect by which CXCR5 (known to be expressed on NSC/NPC[19]) would support proliferation of these cells. Taken together these data are most suggestive that CXCR5 may exert a detrimental effect on maintenance of Nestin and DCX positive cell populations - for example through a pro-apoptotic effect - requiring enhanced proliferation of subgranular zone cells to compensate. A further possibility is that CXCR5 may support differentiation further down a neuronal lineage, thereby 'draining’ the pools of DCX and Nestin positive cells and requiring an enhancement of subgranular zone cell proliferation (Ki67 positive) to replace the pool. An alternative explanation, in which CXCR5 impairs differentiation of proliferating cells into a neuronal lineage is less likely as this effect would not be expected to simultaneously enhance the proliferation of the subgranular zone precursor/stem cells.

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