Role of Perineuronal Nets in Neuronal Plasticity and Repair: Molecular Perspectives on Psychiatric Disorders

INTRODUCTION: Perineuronal nets (PNNs) are extracellular matrix (ECM) structures that wrap fast-spiking parvalbumin-positive (PV⁺) interneurons, which serve in supporting synaptic stability, ion channel modulation, and plasticity critical periods. PNNs are recognized as active regulators of neuronal activity shaped by neural and transcriptional networks. Mutations in their structure, concentration, and sulfation have been linked to some neuropsychiatric disorders, such as schizophrenia, major depressive disorder (MDD), bipolar disorder (BD), and autism spectrum disorder (ASD). This review presents the current knowledge on PNN molecular makeup and their formation after birth, highlighting their roles in neuronal stability, synaptic regulation, and circuit integrity. METHODS: This review was a systematic review of experimental and clinical findings that included postmortem study, genetic, preclinical models, and neuroimaging evidence of the molecular composition, development, and pathological changes in PNNs in brain disorders. RESULTS: Reduced PNN density characterizes schizophrenia, BD, and MDD, linking to excessive synaptic pruning and excitatory-inhibitory imbalance. The elevated level of PNNs in ASD reflects premature circuit stabilization. It reflects the timing of maturation, regional specificity, sulfation patterns, and epigenetic regulation by genetic polymorphisms and multi-omics data. DISCUSSION: PNN remodeling is a response to neural stress and inflammation, which is adaptive and maladaptive. These mechanisms observe the impact of ECM structure on network oscillations, cognition, and disease progression. CONCLUSION: PNNs are therapeutic targets for restoring synaptic integrity and network oscillations. The biomarker discovery, circuit-specific drug delivery, and precision ECM modulation offer the transformative potential for cognitive recovery in CNS disorders.