Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance

The complement system of innate immunity is emerging as a novel player in neurodevelopmental processes. The receptor for C3a, C3aR, shares a close evolutionary and functional relationship with C5a receptors. Whilst the C5a receptor, C5aR1, has been demonstrated to promote embryonic neural stem cell proliferation, little is known about the role of C3aR in this process. Here we show that C3aR is expressed in a similar manner to C5aR1 in mice, at the apical pole of the embryonic ventricular zone, though it has an opposing function. Using in utero delivery of C3aR agonist and antagonist compounds to the embryonic ventricle, we demonstrate that C3aR functions to decrease proliferation of apical neural progenitor cells (NPC). Intriguingly, C3aR(-/-) animals also have altered NPC proliferation, but demonstrate an opposing phenotype to animals subjected to pharmacological blockade of C3aR. Finally, despite a grossly normal development of C3aR(-/- )animals, cognitive behavioural testing of adult mice showed subtle deficits in recall memory. These data demonstrate that in addition to C5a, C3a also has a critical role in the normal development of the mammalian brain.