Therapeutic repetitive transcranial magnetic stimulation (rTMS) is delivered across repeated sessions to induce durable network-level adaptations, yet the cellular mechanisms governing these cumulative effects remain poorly understood. Using mouse organotypic brain cultures, we show that repeated daily intermittent theta burst stimulation with 900 pulses (iTBS900; 10 stimulation sessions over 2 weeks) induces a microglia-dependent adaptive synaptic response in pyramidal neurons. This response is characterized by reduced AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) frequency and decreased dendritic spine density, consistent with adaptive remodeling of excitatory synaptic connectivity. Microglial depletion abolished this homeostatic response and instead resulted in increased synaptic strength and elevated spine density following repeated stimulation. Repeated daily iTBS900 also enhanced microglial uptake and degradative capacity while altering baseline and injury-induced microglial motility, indicating stimulation-dependent changes in microglial surveillance and effector functions. Together, these findings identify microglia as critical mediators of the homeostatic structural and functional adaptations induced by multi-session rTMS.
d'Errico, P., Galanis, C., Kleidonas, D., Elgueta, C., Bartos, M., Vlachos, A.
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