Rouleau, N. | bioRxiv Science

bioRxiv2026

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

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.

biophysics↗

bioRxiv2022

A 3D bioengineered neural tissue model generated from patient-derived iPSCs develops Alzheimer's disease-related phenotypes

BackgroundCurrent models to study Alzheimers disease (AD) include cell cultures and animal models. Human diseases, however, are often poorly reproduced in animal models. Developing techniques to differentiate human brain cells from induced pluripotent stem cells (iPSCs) provides a novel approach to studying AD. Three-dimensional (3D) cultures to model AD are represented by organoids, neurospheroids, and scaffold-based cultures. Some AD-related phenotypes have been identified across 3D models [1]. However, to our knowledge, none of these studies could recapitulate several AD-related hallmarks in one single model and establish a temporal relation among them. Furthermore, to date, the transcriptomic features of these 3D models have not been compared with those of human AD brains. These data are, in our opinion, key to understanding the pertinency of these models for studying AD-related pathomechanisms over time. MethodsWe developed a 3D bioengineered model of iPSC-derived neural tissue that combines a porous scaffold composed of silk fibroin protein with an intercalated collagen hydrogel to support the growth of neurons and glial cells into complex and functional networks. This biomaterial scaffold, designed to match the mechanical properties of brain tissue, can support 3D neural cultures for an extended time without necrosis, a fundamental requisite for aging studies. We have optimized our protocol by seeding neural precursor cells (NPCs) into these scaffolds. NPC-derived cultures were generated from iPSC lines obtained from two subjects carrying the familial AD (FAD) APP London mutation, two well-studied control lines, and an isogenic control. Cultures were analyzed at 2 and 4.5 months. ResultsAn elevated A{beta}42/40 ratio was detected in conditioned media from FAD cultures at both time points, as previously reported in 2D cultures derived from the same FAD lines. However, extracellular A{beta}42 deposition and enhanced neuronal excitability were observed in FAD culture only at 4.5 months. The increased excitability of FAD cultures correlated with extracellular A{beta}42 deposition but not with soluble A{beta}42/40 ratio levels, as they were similar at both time points. These data suggest that extracellular A{beta} deposition may trigger enhanced network activity. Notably, neuronal hyperexcitability has been described in AD patients early in the disease. Transcriptomic analysis revealed the deregulation of multiple gene sets in FAD samples. Notably, such alterations were similar to those observed in human AD brains in a large study that performed a co-expression meta-analysis of harmonized data from Accelerating Medicines Partnership for Alzheimers Disease (AMP-AD) across three independent cohorts. ConclusionsOur 3D tissue model supports the differentiation of healthy iPSC-derived cultures in a porous silk-collagen composite sponge with an optically clear central region. This design facilitates nutrient delivery to meet the metabolic demand of long-term cultures. These data provide evidence that our bioengineered model from patient-derived FAD iPSCs develops time-dependent AD-related phenotypes and establishes a temporal relation among them. Furthermore, FAD iPSC-derived neuronal tissue recapitulates transcriptomic features of AD patients. Thus, our bioengineered neural tissue represents a unique tool to model AD-related pathomechanisms over time, with several advantages compared to the existing models.

neuroscience↗