Human neural models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are essential for advancing research of these fatal neurodegenerative disorders. The advent of iPSC-derived neural systems, from neuronal monocultures to brain and spinal cord organoids, has enabled discoveries that were previously impossible due to the limited availability of live patient CNS tissue, the human-specific RNA-binding of TDP-43, cross-species barriers, and the general inadequacy of animal models of these diseases.
To fully leverage these complex human-derived neural networks, understanding their functional properties, and how these are altered in disease, is a prerequisite. This need is further underscored by recent NIH and FDA policy shifts that prioritize human-based research models, such as organoids and tissue-on-chip platforms, over traditional animal models. As biological research enters this new era, deciphering the functional dynamics of these advanced systems is more important than ever.
In this study we applied our next-generation High-Density Microelectrode Arrays (HD-MEAs), which enable real-time, label-free, and non-invasive electrophysiological recordings with unmatched spatial resolution, allowing to fully characterize and exploit the complexity of these in vitro neural cultures. The MaxTwo multiwell HD-MEA platform, featuring 26,400 electrodes per well, captures activity across entire networks, individual neurons, and subcellular compartments, including axonal arbors.
Using this system, we profiled disease-specific activity in ALS (TDP-43 M337V, Q331K) and FTD (GRN KO) models. The platform’s ultra-dense coverage and industry-leading signal-to-noise ratio (SNR) enabled consistent detection of disease phenotypes with minimal sample replicates. ALS cultures exhibited reduced spontaneous and network activity, while GRN KO neurons displayed pronounced hyperactivity and irregular oscillations, phenotypes that would likely be missed by low-density MEAs due to signal averaging and sparse spatial coverage.
To probe subcellular alterations, we applied our revolutionary AxonTracking assay to extract metrics such as conduction velocity, latency, axonal length, and branching by tracing action potential propagation. GRN KO neurons exhibited significantly shorter, less-branched axons, suggesting that their hyperactivity may represent a compensatory response to structural deficits.
Our HD-MEA platforms combine high-resolution electrophysiology with automated tools for data visualization, batch analysis, and rapid report generation, enabling robust, reproducible phenotyping and screening. This scalable system is ideally suited for acute and longitudinal studies in ALS and FTD research and therapeutic development.
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