Abstracts

Rationale: Human induced pluripotent stem cell (iPSC)-derived brain models are powerful tools for evaluating compound effects on human neuronal function. While traditionally used for neurotoxicity and anti-seizure drug (ASD) screening, current analyses often focus solely on spiking activity. The role of local field potentials (LFPs) in this context remains underutilized, despite their potential to reveal broader network-level changes.

Methods: We utilized functional human iPSC-based neuronal cultures and exposed them to a panel of established ASDs and novel compounds, including cannabidiol. Electrophysiological recordings were performed using multi-electrode array (MEA) technology. Both spiking activity and LFPs were analyzed to evaluate the effects on neuronal excitability and synaptic regulation. Additionally, we modeled epileptogenic conditions to characterize compound-specific modulation of epileptiform activity.

Results: Combined analysis of spiking and LFP data revealed distinct drug-specific signatures, highlighting mechanisms of action related to excitatory/inhibitory balance and neuronal synchronization. LFP metrics provided additional sensitivity to subtle changes in network dynamics not captured by spike-based metrics alone. The model also reliably distinguished epileptiform patterns induced under various pro-convulsive conditions, further supporting its utility in neurotoxicity profiling.

Conclusions: Our findings underscore the value of integrating LFP analysis into iPSC-based electrophysiological platforms for comprehensive assessment of drug effects. This validated assay enables the detection of both therapeutic and adverse epileptogenic effects, offering a more complete understanding of compound action on human neuronal networks and supporting next-generation screening of ASDs.

Funding: Research Without Animals Foundation