Hippocampal C5a-C5aR1 axis drives age-related memory decline via collapsing synaptic chloride homeostasis

The hippocampus is highly vulnerable to brain aging and associated neuroinflammation, a key factor compromising hippocampal plasticity. Specifically, the complement C5a-C5aR1 axis acts as a critical inflammatory convergence point known to impair synaptic function. However, the specific dysregulation of this axis in the aging brain remains poorly understood. In this study, we aimed to characterize the age-dependent dynamics of the hippocampal C5a-C5aR1 axis and investigate its role in age-related memory decline. Our results revealed that the C5a-C5aR1 pathway is aberrantly activated during aging. In human cohorts, elevated plasma C5a levels correlated inversely with memory function, alongside increased C5aR1 expression in aged brains. Additionally, using stereotaxic injection of C5a in young mice and whole-cell patch-clamp recordings in primary hippocampal neurons, we demonstrated that C5a elicited robust brain aging phenotypes, upregulated senescence-associated secretory phenotype markers, and decreased the KCC2/NKCC1 chloride transporter ratio, leading to the suppression of spontaneous inhibitory postsynaptic currents (sIPSCs). These pathological synaptic changes and subsequent spatial memory decline were attenuated following treatment with the specific C5aR1 antagonist PMX205 in senescence-accelerated (SAMP8) mice, which effectively restored KCC2 expression. Our findings suggest that C5a-induced memory decline is driven by the collapse of synaptic chloride homeostasis, highlighting the role of C5aR1 hyperactivation as a crucial driver of GABAergic dysfunction and neuronal hyperexcitability. These results support C5aR1 as a promising therapeutic target for mitigating synaptic deterioration and preserving memory function in the aging brain.