Complement C3a induces synaptic elimination in the hippocampus and neurobehavioral deficits in later life of septic neonatal rats triggered by lipopolysaccharide.

Neonatal septic encephalopathy is a severe complication of sepsis, yet its underlying neuropathological mechanisms remain poorly understood. This study investigated the role of the complement component C3a in mediating synaptic elimination and neurobehavioral deficits in later life of a lipopolysaccharide (LPS)-induced neonatal sepsis model. We found that activated hippocampal astrocytes upregulated C3a expression, while its receptor, C3aR, was elevated in both microglia and neurons. Blocking the C3a/C3aR axis with a C3a receptor antagonist (C3aRA) attenuated cognitive impairments, synaptic loss, and microglial engulfment of synapses. C3a led to downregulated expression of neurofilament medium (NF-M) and an increased accumulation of phosphorylated Tau (p-Tau) in primary neurons in vitro. Mechanistically, C3a activated the ERK signaling pathway in primary neurons. Inhibition of ERK with ASN007 mitigated C3a-induced synaptic elimination, neuronal damage, and behavioral deficits both in vivo and in vitro. Our results suggest that astrocyte-derived C3a may contribute to hippocampal synaptic elimination and cognitive deficits through C3a/C3aR/ERK pathway in later life of neonatal septic rats. These findings highlight the C3a/C3aR/ERK axis as a potential therapeutic target for preventing synaptic and cognitive deficits in neonatal septic encephalopathy.