MICROGLIA-NEURON INTERACTIONS SHAPE INHIBITORY NETWORKS IN PEDIATRIC EPILEPSY

With more than 50 million individuals affected worldwide, epilepsy remains one of the most prevalent neurological disorders. Despite extensive research, its underlying mechanisms remain poorly understood, partly because existing animal models lack translational relevance. This limitation is particularly critical in pediatric epilepsies, where access to living human tissue offers a unique opportunity to investigate disease-specific cellular mechanisms. Approximately 40–50% of drug-resistant childhood epilepsies are associated with malformations of cortical development (MCDs), a heterogeneous group of neurodevelopmental disorders characterized by disrupted cortical organization and frequently accompanied by cognitive impairment. MCDs are associated with alterations in cortical GABAergic networks and profound morphological and molecular changes in microglia. Recent evidence from experimental epilepsy models suggests that microglial signaling pathways may exert protective effects by modulating seizure onset and severity. In this project, we aimed to investigate the contribution of microglia to pediatric epileptogenesis by focusing on microglia-dependent signaling mechanisms and their interaction with cortical GABAergic networks, using an integrative approach combining electrophysiology, electron microscopy, and single-cell RNA sequencing. Electrophysiological recordings revealed that pharmacological modulation of microglia-neurons interactions is associated with changes in inhibitory synaptic activity in cortical pyramidal neurons. Ultrastructural and immunohistochemical analyses uncovered previously unrecognized features of microglial organization and signaling in human cortical tissue. Transcriptomic profiling further indicated molecular programs in microglial subpopulations consistent with the regulation of inhibitory network activity. Altogether, these findings suggest that microglia contribute to the modulation of cortical inhibitory circuits and highlight microglial signaling pathways as promising targets for therapeutic intervention in pediatric epilepsies.