Reversal of repetitive TMS-induced LTP-like plasticity by a novel compound in rats

Repetitive transcranial magnetic stimulation (rTMS) modulates cortical plasticity in a frequency-dependent manner, resulting in predictable and lasting augmentation or attenuation of corticospinal excitability. These rTMS effects on synaptic plasticity are partly mediated by N-methyl-D-aspartate receptors (NMDARs) and share features with long-term depression (LTD) or long-term potentiation (LTP) of excitatory synaptic transmission. In this study, we investigated whether SGE-301 (an NMDR positive allosteric modulator) alters rTMS-mediated motor cortical plasticity in pentobarbital-anesthetized rats. We tested two modalities: 1 Hz for the low-frequency rTMS (lf-rTMS) and 10 Hz for the high-frequency rTMS (hf-rTMS) to induce LTD-like and LTP-like plasticity, respectively. We compared corticospinal excitability before and after rTMS by measuring peak-to-peak motor evoked potential (MEP) amplitudes across a range of stimulator outputs. In the lf-rTMS experiment, the magnitude of the reduction of MEP amplitude was similar between the vehicle and SGE-301 groups. In the hf-rTMS experiment, however, the LTP-like plasticity observed in the vehicle group was completely reversed by SGE-301. In conclusion, SGE-301 engages cortical plasticity mechanisms in vivo and selectively prevents hf-rTMS-induced LTP-like plasticity without altering lf-rTMS-induced LTD-like plasticity. These findings support the utility of preclinical rTMS as a translational tool for detecting central target engagement by neuroplasticity-modulating compounds.