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

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.