Cross-Frequency Magnetic Modulation of Hippocampal Synaptic Plasticity: From Cellular Mechanisms to System-Level Adaptation

Abstract

Highlights What are the main findings? Magnetic stimulation regulates hippocampal synaptic plasticity in a frequency- and state-dependent manner: ELF-MF commonly exerts bidirectional effects with developmental sensitivity, whereas HF-rTMS more consistently restores impaired LTP and related cognitive function under pathological conditions. The effects of cross-frequency magnetic stimulation converge on a multilevel mechanistic framework involving Ca2+ dynamics, BDNF/TrkB-associated neurotrophic and structural remodeling, and system-level adaptation; micromagnetic stimulation extends this modulation to focal, subregional control of the hippocampus. What are the implications of the main findings? The biological effects of hippocampal magnetic stimulation should be interpreted within the combined context of stimulation parameters and network state, rather than on the basis of frequency alone. Standardized parameter mapping, biomarker-guided stratification, and miniaturized or multisite stimulation platforms are needed to support the development of individualized and closed-loop precision neuromodulation strategies. Abstract Magnetic stimulation modulates hippocampal synaptic plasticity in a parameter-dependent manner with effects shaped by stimulation frequency, intensity, waveform, and exposure conditions. Low-intensity magnetic fields generate induced electric fields that can influence neuronal membrane excitability and neural network activity. Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are widely used as important readouts for evaluating the neurobiological effects of magnetic stimulation. Previous studies have shown that extremely low-frequency magnetic fields (ELF-MFs) may enhance, inhibit, or have no effect on LTP. These divergent effects appear to depend on stimulation conditions, developmental stage, and the baseline state of the neural network. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has been reported to promote the recovery of LTP-like plasticity, improve synaptic structure, and regulate the expression of neurotrophic factors in some aging or pathological models. However, its effects are still influenced by both stimulation parameters and biological states. The underlying mechanisms may involve multiple levels of regulation, including Ca2+ dynamics, neurotrophic signals, glutamate receptor dynamics, mitochondrial function, and network oscillations. However, these mechanisms have been inferred mainly from various experimental models, and their interactions, temporal sequence, and causal relationships still need further clarification. Micro-magnetic stimulation (μMS) offers a potential technical approach for improving the spatial selectivity of local regulation in the hippocampus. Arrayed and wireless μMS platforms have further expanded their potential applications. However, available evidence has been obtained primarily from in vitro experiments and animal models. This review summarizes the effects of magnetic stimulation with different parameter configurations on hippocampal synaptic plasticity, integrates the biological mechanisms underlying cross-frequency magnetic neuromodulation, and discusses current challenges in the field of magnetic neuromodulation and future directions toward translational development.