Microglial Cytokines Mediate Plasticity Induced by 10 Hz Repetitive Magnetic Stimulation

Abstract

Microglia-the resident immune cells of the central nervous system-sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain-region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically employed non-invasive brain stimulation technique, on microglia-mediated synaptic plasticity. 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from microglia in mouse organotypic brain tissue cultures of both sexes, while no significant changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings, in vivo depletion of microglia abolished rTMS-induced changes in neurotransmission in the medial prefrontal cortex (mPFC) of anesthetized mice of both sexes. We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia.Significance Statement:Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that induces cortical plasticity. Despite its wide use in neuroscience and clinical practice (e.g., depression treatment) the cellular and molecular mechanisms of rTMS-mediated plasticity remain not well understood. Herein, we report an important role of microglia and plasticity-promoting cytokines in synaptic plasticity induced by 10 Hz rTMS in organotypic slice cultures and anesthetized mice, thereby identifying microglia-mediated synaptic adaptation as a target of rTMS-based interventions.

Axon morphology and intrinsic cellular properties determine repetitive transcranial magnetic stimulation threshold for plasticity

“…When examining the dendritic architecture of CA1 neurons in mice and rats, and employing a standardized artificial axon across all cells (c.f., [16,29,30]), our simulations revealed no significant difference in the depolarization threshold elicited by rMS (Fig. 6A, B).…”

“…Specifically, complete reconstructions of axons are of utmost importance for precise evaluation of rTMS outcomes, considering their substantial interaction with the electric field [51]. Previous studies, including our own work, often relied on artificial or simplified axon morphologies [16, 29–31]. Importantly, our investigation revealed no significant differences in axons of cultured CA1 neurons between mice and rats.…”

“…Individual CA1 pyramidal neurons were patched and AMPA receptor mediated mEPSCs were recorded 2 – 4 h after stimulation. In line with our previous work [c.f., [11,16,35,36]] a significant increase in mean mEPSC amplitude was observed as compared to age-/time-matched control cultures that were treated in the exact same way except for rMS (control; Figure 1D-E).…”

“…We propose the possibility of “super-responder cells” within complex cortical networks–cells highly responsive to rTMS at specific stimulation intensities. This notion finds support in the observation that not all neurons of this and our previous studies (c.f., [11,13,16,36]) displayed elevated mEPSC amplitudes or decreased mIPSC within the 2 – 4 h following stimulation.…”

“…Despite its increasing use for treating neuropsychiatric disorders such as major depression [4–8], the cellular and molecular mechanisms of rTMS in human cortical networks remain not well understood [9,10]. Animal models, both in vivo and in vitro, have provided important insights into mechanisms by which rTMS modifies neuronal circuit excitability and plasticity [11–16]. It has been shown for example that rTMS affects the functional and structural properties of excitatory and inhibitory synapses [11,13,17], and that it facilitates the reorganisation of abnormal cortical circuits [18,19].…”