WONOEP XVII appraisal: The role of the extracellular matrix in epilepsy

The extracellular matrix (ECM) is composed of proteoglycans and glycoproteins that regulate the external environment surrounding neurons, glia, and the vascular system. The ECM is vital for maintaining the structure and function of the brain and also acts as a reservoir for various signaling molecules and neurotransmitters, modulating synaptic transmission and plasticity. Recent research highlights the important role of ECM proteins in both brain development and various neurological diseases, including epilepsy. Alterations in ECM composition and subsequent remodeling may disrupt physiological network excitability and synaptic connectivity, triggering neuroinflammation with active participation from glial cells, including astrocytes and microglia, and blood-brain barrier function. This influences neuronal function and contributes to the formation of epileptic foci and the development of drug-resistant epilepsy. Understanding the intricate interplay between the ECM and epilepsy may enable the identification of novel biomarkers and development of therapeutic strategies targeting this dynamic microenvironment. In this review, we provide a summary of the discussions held at the XVII Workshop on Neurobiology of Epilepsy (WONOEP), organized in 2023 by the International League Against Epilepsy, on the role of the extracellular space in epilepsy. Specifically, we summarize recent advances in understanding the ECM, its alterations in epilepsy, advanced imaging and omics tools for ECM analysis, and the implications for the development of ECM-based therapeutics and biomarkers for acquired and genetic forms of epilepsy. To complement the material presented at WONOEP, we performed targeted, nonsystematic literature searches in PubMed using topic-specific terms (e.g., "perineuronal nets", "extracellular matrix", "traumatic brain injury", "post-traumatic epilepsy", "chloride") and citation tracking to ensure that key experimental and translational studies relevant to these themes were included.