Cerebellar Microglial Metabolic–Inflammatory Coupling Drives Network Progression in Temporal Lobe Epilepsy

Objective Temporal lobe epilepsy (TLE) is increasingly recognized as a network disorder that extends beyond the hippocampus. Among the extra-hippocampal regions, the cerebellum has emerged as a remote yet functionally connected node showing consistent metabolic alterations. However, its mechanistic contribution to seizure propagation and disease progression remains largely unclear. The aim of this study was to elucidate the contribution of cerebellar microglial activation to aberrant glucose metabolism and to determine whether metabolic-inflammatory coupling within the cerebellum drives seizure generalization and cognitive decline in TLE. Methods We integrated [ 18 F]FDG PET analysis from 55 patients with TLE and a lithium chloride-pilocarpine rat model of TLE to delineate cerebellar metabolic abnormalities across disease stages. Longitudinal [ 18 F]FDG and [ 18 F]DPA-714 microPET/CT imaging was performed to assess glucose metabolism and microglial activation. Histological and flow cytometric analyses characterized microglial phenotypes. Cerebellar mRNA sequencing with KEGG pathway enrichment analysis and hub gene identification using Cytoscape identified c-Fos as a central regulator of MAPK signaling, which was functionally validated via stereotactic cerebellar administration of the c-Fos inhibitor T-5224. Results Patients with TLE exhibited bilateral cerebellar hypermetabolism. In rats with chronic TLE, elevated [ 18 F]FDG and [ 18 F]DPA-714 uptake in the cerebellum was confirmed, accompanied by Purkinje cell loss and increased proinflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-12p70). Pharmacological inhibition with minocycline or T-5224 normalized cerebellar PET signals, attenuated M1-like microglial polarization, reduced seizure frequency, and improved spatial and recognition memory. Conclusion These findings identify cerebellar metabolic-inflammatory coupling, driven by c-Fos-dependent microglial activation, as a key mechanism promoting epileptic network progression. Targeting this cerebellar axis provides a promising therapeutic avenue for precision neuromodulation in TLE.