High-Frequency Electrical Stimulation Elicits Distinct Response Modes Via Synaptic Interplay.

High-Frequency electrical stimulation (HFS) has gained prominence as a powerful neuromodulation technique with multiple therapeutic interventions, yet its mechanisms of action and interaction with synaptic circuitry remain unclear. In this study, we examined how 2 kHz HFS interacts with excitatory and inhibitory signaling. We targeted retinal ganglion neurons as they preserve intact synaptic circuits and single-cell recordings via whole-cell patch clamping are readily achievable, making them an ideal model for investigating HFS-induced modulation in physiologically relevant conditions. Our findings reveal that HFS induces multiple distinct response mode, including (1) selectively enhanced excitability during the excitatory phase, (2) similarly elevated activation level in both excitatory and inhibitory phases, and (3) a somewhat paradoxical pattern wherein excitatory-phase firing is suppressed while neuronal firing escalates during inhibitory phases. Moreover, we also found that HFS-based modulation depends on temporal profiles of synaptic input and/or intrinsic properties of each cell type. By investigating how HFS modulates neuronal excitability in physiologically relevant conditions, this work provides a foundation for developing more refined and effective neuromodulation protocols.Clinical Relevance- Our results highlight the intricate interplay between HFS and synaptic signaling in shaping neuronal excitability, suggesting the importance of considering these dynamics when designing stimulus protocols. Additionally, HFS's ability to induce diverse response modes presents flexible strategies for targeting various dysregulated neural circuits.