Human neuron-microglia system as a potential seizure-on-chip model

• Applicant: Rouhollah Habibey, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570473791

Microglia are the most important immunoregulatory glial cells in the brain. A wide range of functions, from maintaining brain homeostasis to neuroprotection, have been attributed to resident microglia in the brain. Microglia also sense neuronal hyperexcitability and modify network activity. Depletion or inhibition of microglia increases neuronal excitability and network susceptibility to seizure discharges. Species-specific differences of microglia make it difficult to extrapolate findings from mouse models to humans. Such differences underscore the importance of human-derived microglia-neuron culture systems to establish a reliable preclinical model for screening microglia-targeted drug candidates. A characteristic functional feature of the developing prenatal brain is periodic spontaneous activity, so-called network bursts, which resemble synchronous discharges during seizure events. Burst activity disappears after birth and its persistence may be the electrophysiological hallmark of pathological conditions such as epilepsy and seizures. In contrast, burst activity in cultured neuronal networks does not disappear. Instead, burst synchrony increases with the age of the culture. Therefore, an optimal in vitro model that represents the onset of burst activity, its peak and subsequent decline is lacking. Current culture models are neuron-astrocyte-based and other cell types, such as microglia are not included. Here, I will investigate whether long-term interaction of microglia with the developing neuronal network can modify the burst activity profile. The results of my project will be extended to modeling seizures in a microglia-based in vitro system. I will use brain-on-chip approaches that allow the integration of different cell types (neurons, astrocytes and microglia) in a physically defined microfluidic microenvironment. Human iPSC-derived cultures within compartmentalized microfluidic devices will be further integrated with multi-electrode array (MEA) electrophysiology to enable long-term functional analysis of neuron-microglia interactions.

• DFG Programme: Research Grants