Cell-type-specific CB1R signaling modulates prefrontal synaptic responses to HF-rTMS in chronically stressed mice

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is an effective treatment for depression, but its synaptic mechanisms remain incompletely understood. Using a chronic unpredictable mild stress (CUMS) mouse model, we investigated whether cannabinoid receptor 1 (CB1R) signaling in distinct neuronal populations contributes to the amelioration of depressive-like behaviors by HF-rTMS through modulation of prefrontal inhibitory synaptic transmission. Behavioral assessments were combined with whole-cell patch-clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSC) in prefrontal cortex pyramidal neurons, along with systemic pharmacological CB1R blockade (AM281) and conditional knockout mice with deletion of CB1R in glutamatergic (vGlut1-CB1R-KO) or GABAergic (GAD2-CB1R-KO) neuronal populations. sIPSC frequency and amplitude were analyzed as indirect indices of presynaptic release and postsynaptic receptor function, respectively. HF-rTMS ameliorated CUMS-induced depressive-like behaviors and partially normalized sIPSC alterations (frequency and amplitude), which were attenuated by AM281. In vGlut1-CB1R-KO mice, baseline sIPSC frequency was reduced and half-width prolonged; CUMS exacerbated these alterations and induced anhedonia/anxiety, yet HF-rTMS failed to rescue any behavioral or synaptic changes. In contrast, GAD2-CB1R-KO mice exhibited baseline anxiety-like behavior accompanied by increased sIPSC frequency, consistent with loss of presynaptic CB1R-mediated suppression of GABA release, but showed attenuated-CUMS-induced depressive-like behaviors,; HF-rTMS partially modulated postsynaptic function (increased amplitude, accelerated kinetics). These findings suggest that glutamatergic CB1R signaling contributes to the ability of HF-rTMS to modulate presynaptic inhibitory function. Meanwhile, GABAergic CB1R ablation is accompanied by reduced behavioral vulnerability to chronic stress and may shift HF-rTMS actions toward potential postsynaptic modulatory processes. Collectively, these observations implicate cell-type-specific CB1R signaling in shaping the synaptic responses of prefrontal inhibitory circuits to HF-rTMS.