1 Hz Low‐Frequency Repetitive Transcranial Magnetic Stimulation Ameliorates Epilepsy by Suppressing Interferon‐γ Signaling‐Dependent Microglial Synaptic Phagocytosis in Mice

Aims We aim to investigate the impact of low‐frequency repetitive transcranial magnetic stimulation (LF‐rTMS) on activated microglia in temporal lobe epilepsy (TLE), which exacerbate seizures and memory problems, and to explore the molecular mechanisms and clinical potential of LF‐rTMS for TLE treatment. Methods We tested 0.3, 0.5, 1 Hz LF‐rTMS in kainic acid (KA)‐induced TLE mice, assessing EEG, inflammation, synaptic phagocytosis, memory, scRNA‐seq, and IFN‐γ neutralizing antibodies. SnRNA‐seq of human hippocampal sclerosis (HS) tissues confirmed relevance. Results In KA‐induced TLE mice, 1 Hz LF‐rTMS decreased seizures, neuroinflammation, and hippocampal synaptic phagocytosis, while enhancing memory. These effects were linked to increased microglial IFN‐γ signaling (activating STAT2 and inhibiting CADM1/2/3), which were negated by IFN‐γ blockade. SnRNA‐seq of human HS tissues revealed elevated IFN‐γ signaling in DAM‐like cells, indicating clinical relevance. Conclusion Our study indicates that 1 Hz LF‐rTMS is a promising treatment for TLE, potentially reducing seizures and cognitive issues by affecting microglial function. Our findings show that IFN‐γ signaling triggers STAT2 activation, which is strongly linked to the increased expression of IFN‐γ signature DAM and the decreased expression of CADM1/2/3 in DAM, thus playing a role in the neuroprotective effects of 1 Hz LF‐rTMS. These findings reveal a new LF‐rTMS mechanism and offer insights for targeted therapies in drug‐resistant epilepsy.