Orchestrating the Matrix: the role of Glial Cells and Systemic Signals in Perineuronal Net Dynamics

Perineuronal nets (PNNs) are specialized, dense extracellular matrix structures that enmesh the cell bodies and dendrites of specific neurons, most notably inhibitory interneurons. Increasing evidence indicates that PNNs serve not merely as passive scaffolds but play an active and essential role in modulating synaptic plasticity and circuit physiology. They critically influence the timing of sensory system critical periods, as well as processes underlying learning, memory, and higher cognitive functions. Furthermore, dysregulation of PNN density and architecture have been associated with conditions like autism, neurodevelopmental disorders, schizophrenia and Alzheimer’s disease. Since they are extensively involved in brain function, we discuss the multitude of regulatory factors that govern the formation, maturation, and remodeling of PNNs. In particular, we focus on both molecular and cellular brain-intrinsic mechanisms, highlighting the potential contributions of microglia and astrocyte derived factors. Additionally, we consider the influence of long-range signaling cues, including the metabolic status and peripheral hormones. Analysing this complex network of interactors, we try to highlight the role of PNNs beyond neural plasticity and brain function, in a broader whole-body physiological perspective.