Perineuronal Nets in Neuropsychiatric Disorders

Perineuronal nets (PNNs) are specialized extracellular matrix structures that enwrap select neuronal populations—particularly, parvalbumin‐positive inhibitory interneurons. Under physiological conditions, they stabilize synaptic connectivity, regulate excitatory–inhibitory balance, and contribute to the closure of developmental critical periods. Rather than being static scaffolds, PNNs dynamically regulate neuronal excitability, synaptic plasticity, and circuit maturation across the lifespan. Notably, accumulating evidence indicates that the disruption of these functions represents a cross‐diagnostic mechanism underlying shared circuit vulnerabilities across multiple brain disorders. In autism spectrum disorder, schizophrenia, bipolar disorder, epilepsy, Alzheimer’s disease, amyotrophic lateral sclerosis, and substance use disorders, alterations in PNN density, composition, and remodeling are consistently associated with disrupted PV interneuron function, impaired network oscillations, and aberrant circuit stability. A central paradox thus emerges: excessive PNN stabilization may prematurely restrict plasticity during development, whereas pathological degradation or dysregulation in adulthood destabilizes mature circuits and increases vulnerability to excitotoxicity, neuroinflammation, and maladaptive memory persistence. These context‐dependent effects highlight the translational potential of targeting PNNs to restore circuit balance. Together, these findings position PNNs as critical regulators of the balance between stability and adaptability in neural circuits and underscore their potential as translational targets for circuit‐level therapeutic interventions.