Unravelling microglia-specific contributions to neuronal network activity: Engineering a human stem cell-derived tri-culture on microelectrode arrays

Neuronal development and function is regulated by a complex interplay between neurons and glial cells. Microglia are the tissue-resident immune cells of the central nervous system bridging immunological and neuronal activity. In recent years, the involvement of microglia in a variety of neurological and psychiatric disorders has been increasingly highlighted. However, understanding microglia-specific contributions to neuronal activity in humans remains challenging. A promising tool to gain mechanistic insight into how microglial cells shape neuronal networks and their activity is combining microelectrode array technology with human stem cell modeling. Here, we show our strategy to engineer composite networks consisting of human stem cell derived- neurons, astrocytes, and microglia that are reproducible and long-term viable. We record neuronal network activity using microelectrode arrays, which enables functional phenotyping of the networks during development. Since a hallmark of microglial function is their capability to rapidly respond to changes in the brain environment, we explore microglia-neuronal crosstalk in a context-dependent manner. Analysing microglia regulation of neuronal activity will contribute to our understanding of neuro-immune interactions in health and disease, and the potential of targeting these interactions for novel treatment strategies in neurological and psychiatric disorders.