Repetitive magnetic stimulation induces synaptic plasticity through cooperative pre- and postsynaptic activation

Abstract

Abstract Repetitive TMS (rTMS) induces changes in cortical excitability. However, the cellular and molecular mechanisms which underlie rTMS-induced plasticity remain incompletely understood. Using a combination of functional optical imaging, electrophysiological recordings, and multi-scale computational modeling we study how the physical input parameters of rTMS affect the ability of neurons to express synaptic plasticity. Our experiments in pyramidal neurons of mouse organotypic tissue cultures show that a cooperative pre- and postsynaptic activation during stimulation asserts metaplastic effects, which result in robust LTP-induction. At the molecular level we demonstrate that these effects depend on the activation of NMDA receptors, L-type voltage gated calcium channels and functional intracellular calcium stores. Finally, a computational model that is based on a voltage-dependent STDP rule with fast BCM-like metaplasticity reproduces our findings, and predicts biological differences between 10 Hz and iTBS protocols. These results confirm and expand upon our previous work on rTMS-induced synaptic plasticity in animal models. They provide a framework towards the development of multi-scale computational models that can predict biological effects of rTMS. Keywords: LTP, STDP, Metaplasticity, Multi-scale computational modeling