Hippocampal neurogenesis occurs within the subgranular zone of the dentate gyrus and is important for learning and memory. Neurogenesis is impaired in many pathological conditions; an observation that may account for learning and memory deficits in patients suffering from these conditions. Studies on immune-deficient mice show reduced hippocampal neurogenesis and associated learning and memory impairments in mice devoid of CD4+ T lymphocytes. Neuropeptides are potential candidates for mediating neuro-immune interactions. Vasoactive Intestinal Peptide (VIP) is a neuropeptide, released by firing interneurons from the stem cell niche, that modulates hippocampal neurogenesis via VPAC1/2 receptors. VIP receptors are also present on T lymphocytes. Microglia are innate immune cells that regulate hippocampal neurogenesis. They are ideally placed to communicate with T lymphocytes that normally reside outwith the brain parenchyma. Given the nescience underlying T lymphocyte regulation of hippocampal neurogenesis, we sought to investigate the hypothesis that VIP modulates T lymphocytes to release cytokines to regulate hippocampal neurogenesis via interaction with microglia. We have shown that T lymphocytes supernatant increases the proliferation of hippocampal nestin-expressing cells. This effect is further enhanced under VIP treatment via VPAC1 receptor subtype. Examining possible cytokine involvement, we found that IL-4 mediates proliferation. Using Mac-1-SAP to deplete resident microglia, we demonstrated that supernatant acts primarily via microglia to increase supernatant effects. T lymphocytes induce microglia to upregulate cytokines and mediators such as IL-10 and BDNF. Phenotyping showed an additional neurogenic effect under VIP treated supernatant. Our results show VPAC1 receptor subtype expressed by CD4+ T lymphocytes mediates VIP proliferative effects on hippocampal precursor cells via IL-4 cytokine release. Microglia are key for mediating this effect via release of mediators. The findings of this study implicate a novel mechanism for VPAC1 CD4+ T lymphocyte receptor as a neuro-immune mediator of hippocampal neurogenesis, and from a therapeutic perspective, shows that the effect can be pharmacologically manipulated.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:629826 |
| Date | January 2014 |
| Creators | Khan, Damla |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/66138/ |
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