Dynamic astrocytic complement C3 activation in the epileptic hippocampus

Complement C3 plays important roles in neuroinflammation and is significantly upregulated in hippocampal tissues from patients with mesial temporal lobe epilepsy (mTLE) that is characterized by neuronal loss and gliosis. However, the temporal and spatial expression of complement C3 in the epileptic brain remain unclear. In this study, we first confirmed the upregulation of C3 in resected hippocampal tissues encompassing the CA1-CA4 regions from patients with mTLE with hippocampal sclerosis (mTLE-HS) using RNA sequencing, and in an mTLE mouse model using microarray data from the GEO database. Using a novel floxed C3-IRES-Tdtomato knock-in mouse line, we identified sustained C3 overexpression mainly in reactive astrocytes within the hippocampal stratum lacunosum-moleculare. This activation emerged 3 days after pilocarpine-induced status epilepticus, progressively extended to the CA1 region by 3 weeks, and highlighted region- and stage-specific dysregulation of C3 during epileptogenesis.