title: Microglial VPAC1R mediates a novel mechanism of neuroimmune-modulation of hippocampal precursor cells via IL-4 release.
abstract: Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro-neurogenic effect of microglia via the VPAC1 receptor. This VIP-induced enhancement is mediated by IL-4 release, which directly targets NSPCs. This demonstrates a potential neuro-immuno-neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease.
authors.affiliation: Division of Clinical Neurosciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Nunan
authors.forename: Harri
authors.initials: H
authors.lastname: Sivasathiaseelan
authors.forename: Damla
authors.initials: D
authors.lastname: Khan
authors.forename: Malik
authors.initials: M
authors.lastname: Zaben
authors.forename: William
authors.initials: W
authors.lastname: Gray
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D006624:Hippocampus / Q000276:immunology*; D015847:Interleukin-4 / Q000378:metabolism*; D017628:Microglia / Q000276:immunology*; D058953:Neural Stem Cells / Q000276:immunology*; D015213:Neuroimmunomodulation / Q000502:physiology*; D017208:Rats, Wistar; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495508:Vipr1 protein, rat; D015847:Interleukin-4; D014660:Vasoactive Intestinal Peptide
keywords: VIP; cell culture; microglia; neurogenesis