LTP-patterned electromagnetic stimulation induces NMDA receptor-dependent synaptic plasticity in cortical networks

Abstract

Bioinspired electromagnetic stimulation, in which fields are patterned after endogenous neural activity, have emerged as a potential non-invasive approach for modulating brain dynamics, yet the waveform parameters that determine biological specificity remain poorly defined. Complex electromagnetic patterns modeled after long-term potentiation (LTP) have been reported to alter learning and cortical injury outcomes in vivo, yet whether these fields engage cell-scale synaptic plasticity mechanisms remains unclear. Here, we show that a microtesla-strength electromagnetic field (EMF) patterned after electrophysiological signatures of long-term potentiation produces complex waveform-specific changes in primary cortical network dynamics. Using high-density microelectrode arrays, we show that LTP-patterned EMF stimulation transiently increases spontaneous spikes-per-burst activity relative to a frequency-matched sine-wave EMF exposure and a sham, no field control. This waveform-dependent effect was abolished by NMDA receptor antagonism, indicating dependence on glutamatergic signaling pathways linked to activity-dependent plasticity. LTP-EMF stimulation also dynamically altered evoked network responses, reducing active electrode recruitment to direct electrical stimulation immediately after exposure, with recovery at later timepoints, consistent with a reversible post-induction reorganisation of network state. Transcriptional profiling identified a delayed adaptive response enriched for cellular remodeling pathways, and immunocytochemistry revealed increased co-localization of pre- and post-synaptic markers synaptophysin and PSD-95, a microstructural hallmark of synaptogenesis. Overall, these findings show that weak, bioinspired EMF stimulation can induce waveform-specific changes in cortical network dynamics and engage NMDA-dependent, plasticity-associated mechanisms. This work supports the perspective that temporal waveform structure is a key stimulation parameter for optimizing non-invasive electromagnetic modulation of neural activity.