The role of the perineuronal net in pathological mechanisms of neurological and psychiatric disorders

The perineuronal net is a unique extracellular matrix mostly located around certain neurons in the central nervous system, predominantly encompassing parvalbumin-positive interneurons and pyramidal neurons in specific brain areas. Composed of characteristic molecular constituents such as chondroitin sulfate proteoglycans, hyaluronan, tenascins, and link proteins, the perineuronal net plays a critical role in modulating various aspects of neuronal and cognitive functions. Accumulating evidence has demonstrated its involvement in ion homeostasis, protection against oxidative stress and inflammation, and the regulation of synaptic plasticity. In addition, several regulatory factors are essential for preserving the structural integrity and physiological functions of the perineuronal net. Importantly, dysregulation of the perineuronal net has been implicated in the pathophysiology of various neurological and psychiatric disorders. Therefore, elucidating the mechanisms underlying the perineuronal net regulation may offer novel therapeutic strategies for treating neurological conditions that currently lack effective interventions. This review summarizes recent advances in the perineuronal net research and underscores its emerging physiological, clinical, and therapeutic relevance.