The complement system, traditionally considered a peripheral component of the body's innate immune response, comprises approximately 50 membrane-bound and soluble proteins that form a rapid and potent enzymatic cascade. This cascade facilitates the opsonisation, phagocytosis, and osmotic lysis of invading pathogens and detrimental host tissue. Recent evidence demonstrates that the complement system is not restricted to peripheral tissues; indeed, several complement receptors are expressed in the adult brain. Multiple complement factors, such as C1q and C3, participate in the opsonisation of targeted synapses in the healthy murine central nervous system, enabling microglial synaptic phagocytosis and the refinement of the adult connectome. Other complement activation components, including C5a and its associated G-protein-coupled receptor C5aR1, are expressed in neurons within the healthy brain. However, the neuronal expression of these factors remains a subject of debate in the scientific community, and the neurophysiological role of C5aR1 has yet to be elucidated.In this thesis, novel C5aR1-targeted molecular probes were developed with the objective of enhancing the current tools for visualising C5aR1. The chapter aimed to develop and validate a molecular probe capable of accurately visualising C5aR1 by leveraging the highly specific class of "PMX" ligands, a group of potent C5aR1 antagonists. Two synthesized molecular probes exhibited specific fluorescent properties while maintaining exceptional antagonistic function: PMX402 (Atto488- F[OP(dCha)WR]) and PMX403 (FAM-F[OP(dCha)WR]). The creation of these probes sought to corroborate reports of neuronal C5aR1 expression. Although the molecular probes demonstrated remarkable fluorescence in both human and mouse C5aR1 when expressed at moderate to high levels, the fluorescence intensity in the neuronal cell line SH-SY5Y was insufficient for the visualisation of a discernible fluorescent signal, potentially due to the lower native expression of C5aR1 on this cell line.The complement system has recently been posited to serve a crucial function in the neurophysiology of the healthy brain. Despite these emerging insights, a comprehensive electrophysiological examination of neuronal C5aR1 has not yet been conducted. Therefore, whole-cell electrophysiology was employed to explore the potential role of C5aR1 in healthy adult brain physiology. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from layer 5 pyramidal neurons in the primary motor cortex of adult wild-type (WT) and C5aR1-knockout mice using whole-cell electrophysiology. Our findings revealed that animals lacking C5aR1 exhibited significantly longer sEPSC inter-event intervals than their WT counterparts in pyramidal neurons, suggesting that C5aR1 may contribute to maintaining or enhancing excitatory inputs in these neurons. Similarly, acute pharmacological inhibition of C5aR1 with PMX53 in WT pyramidal neurons also increased sEPSC inter-event interval lengths, indicating that C5aR1 signalling may be required for proper excitatory synaptic transmission. Intriguingly, despite these observations, neither acute nor 1-hour exposure of WT neurons to exogenous C5a resulted in increased sEPSC inter-event intervals, suggesting the possibility of constitutive activity of C5aR1 or a ligand-independent role for this receptor. Continuing this investigative line, the next chapter sought to determine if these C5aR1-modualtory effects were calcium-dependent. By employing both the calcium-independent metric, the measurement of miniature EPSCs, and the calcium dependent metric, paired-pulse facilitation, it was found that antagonism of C5aR1 reduced spontaneous neurotransmitter release but had no effect on paired pulse ratios in layer 5 pyramidal neurons. These findings indicate that C5aR1 is likely modulating synaptic transmission through calcium-independent processes.In conclusion, our findings indicate that neuronally-expressed C5a receptors possess a functional neurophysiological role, as pyramidal neurons with either genetic deficiency in C5aR1 or pharmacological inhibition via C5aR1 antagonists exhibit reduced excitatory synaptic transmission. This evidence supports recent discoveries suggesting that the complement system may play a crucial role in the physiology of the healthy brain. Our observations concerning C5aR1 contribute additional evidence for a neuronally-expressed G-protein-coupled receptor, which plays a role in maintaining excitatory input in cortical pyramidal neurons. Considering the significant evidence implicating C5aR1 in a variety of neurological disorders, as well as the recent approval of complement-targeted therapeutics for neurological inflammatory diseases such as myasthenia gravis and neuromyelitis optica spectrum disorders, it is crucial to expand our knowledge of C5aR1's role in normal neurophysiological functions. This research holds particular relevance in light of these clinical advancements, and by gaining a deeper understanding of C5aR1 it will aid in assessing and potentially mitigating any adverse effects that may arise from these therapeutic interventions.