Neuroimmune regulation of adult hippocampal neurogenesis by Complement Component 3 and Complement C3a Receptor

New neurons are added to the dentate gyrus of the hippocampus throughout adult life, through the process known as adult hippocampal neurogenesis (AHN). This important form of structural plasticity supports learning and memory in mammalian species. AHN is tightly regulated by a myriad of factors, including the immune system. Previous evidence suggests that signalling via Complement Component 3 (C3) and Complement C3a Receptor (C3aR) may regulate AHN under physiological conditions, although the mechanism of this putative regulation is unclear. In addition, C3a/C3aR signalling may regulate neuronal morphology. Using C3-/- and C3aR-/- mice, I used a combined in vitro and in vivo approach to investigate the role of C3/C3aR signalling in AHN. In Chapter 2, I demonstrate that C3a/C3aR signalling is able to directly influence hippocampal precursor cells in primary cultures. Furthermore, in the adult mouse brain, there is an increase in the number of immature neurons in the absence of C3 and C3aR, suggesting that C3a/C3aR signalling exerts an anti-neurogenic effect in the healthy brain. In Chapter 3 I report that the dendritic arborisation of newborn neurons is altered in the absence of C3aR, but not C3, suggesting involvement of an alternative ligand. Therefore, C3aR signalling via an as yet-unidentified ligand is important for maintaining the normal neuronal morphology of adult born neurons. Both the net levels of AHN and immature neuronal morphology have important functional consequences for cognitive and affective processes involving the hippocampus, which I investigate in Chapter 4. I report superior performance of C3-/- and C3aR-/- mice in a hippocampus-dependent spatial discrimination task, consistent with their elevated levels of AHN. Furthermore, C3a/C3aR deficiency was associated with abnormal anxiety phenotypes. In conclusion,these results demonstrate a novel mechanism for neuroimmune regulation of AHN, which is of functional consequence to learning, memory and affective behaviour