Complement C3aR in adolescent synaptic pruning and risk for anxiety

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Anxiety disorders represent some of the most common and increasing health problems worldwide. Because their causes are poorly understood, current treatments are of limited benefit in a significant proportion of cases and thus there is an urgent need for more effective, targeted therapies. Anxiety disorders typically emerge during the teenage years and affected adolescents are at increased risk for other mental health disorders later in life. During adolescence, the brain undergoes significant changes in its structure and function brought about via a process known as 'synaptic pruning'. This process ensures that synapses (the connections between brain cells) that are infrequently used are eliminated or 'pruned', allowing the remaining connections to mature. We now know that the immune system, and in particular a branch known as complement (https://www.youtube.com/watch?v=BSypUV6QUNw&feature=emb_title) is critical to this process. Complement drives synaptic pruning by tagging weak synapses, which are then engulfed or 'phagocytosed' by microglia, the brain's immune cells. This process is essential for healthy brain function but there is potential for neuronal networks to be disturbed should the process go awry, which may contribute to the development of mental disorders. In this work we will investigate how a molecule known as the C3a receptor (C3aR), a member of the complement system, controls synaptic pruning during adolescence to influence the development of anxiety. Previously, we have found a novel role for C3aR in anxiety, whereby mice deficient in this receptor display increased anxiety. In addition, these mice have a reduced number of synapses throughout the brain. When their microglia were tested in the lab, these cells engulfed more synaptic proteins. This suggests that C3aR controls microglial phagocytosis, and we predict that reduced C3aR function leads to excessive synaptic pruning during adolescence leading to synapse loss and elevated anxiety.However, there are critical gaps in our knowledge which we must first address before we can test this prediction. So far, animal studies have measured complement driven synaptic pruning only during very early stages of brain development, roughly equivalent to human infancy, but there has been much less focus on adolescent brain development. Importantly, there is no existing information on adolescent synaptic pruning within brain areas implicated in anxiety such as the amygdala and hippocampus, which do not mature until adolescence. In this project, we will characterise the precise timing of synaptic pruning in these brain areas during adolescence, by documenting the evolving state of complement, synapse number and microglial engulfment over this period. We will then be able to test our prediction that reduced C3aR results in greater synapse engulfment in brain areas related to anxiety. Finally, the long-term effects of excessive synaptic pruning have not been well characterised but are likely to result in altered brain circuits and therefore abnormal functioning of brain networks. To this end, we will investigate the brain-wide effects of excessive synaptic pruning in C3aR-deficient mice at both adolescence and adulthood using clinically relevant brain imaging measures of brain structure and function. These studies will deliver much-needed information on the neurobiological mechanisms of anxiety, providing insight into how complement and synaptic pruning impact anxiety-associated brain areas during adolescence. Importantly, the data generated will be essential to inform our future work in which we aim to reduce excessive microglial synaptic pruning in C3aR-deficient mice to determine whether it prevents abnormal anxiety from developing. If so, drugs that enhance C3aR function could provide a novel means of treating anxiety and disorders associated with abnormal synaptic pruning.