Extracellular Origins of Cognition: Lessons from Primate Neocortical ECM

The brain's extracellular matrix (ECM) is an intricate and dynamic network that plays essential roles in neurodevelopment, synaptic plasticity, and circuit stability. Despite its importance, the molecular composition and spatial organization of the developing brain ECM remain poorly characterized. In this commentary, we highlight the recent study by Vilicich et al., which employs a multi-modal approach, integrating single-cell transcriptomics, proteomics, and immunohistofluorescence, to construct a map of the ECM in the developing neocortex of humans and non-human primates. By curating a comprehensive list of extracellular proteins termed the “Exomatrix” and analyzing their distribution across cortical layers and developmental stages, the authors reveal layer-specific and evolutionarily conserved ECM features. These findings not only expand our understanding of ECM's role in shaping the brain during early development but also emphasize its potential involvement in the pathogenesis of neurodevelopmental disorders, urging further research into ECM biology as a frontier in neuroscience.