The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders

Perineuronal nets (PNN) are extracellular matrix (ECM) assemblies that preferentially ensheath parvalbumin (PV) expressing interneurons. Converging evidence indicates that PV cells and PNN are impaired in a variety of neurological disorders. PNN development and maintenance is necessary for a number of processes within the CNS, including regulation of GABAergic cell function, protection of neurons from oxidative stress, and closure of developmental critical period plasticity windows. Understanding PNN functions may be essential for characterizing the mechanisms of altered cortical excitability observed in neurodegenerative and neurodevelopmental disorders. Indeed, PNN abnormalities have been observed in post-mortem brain tissues of patients with schizophrenia and Alzheimer’s disease. There is impaired development of PNNs and enhanced activity of its key regulator matrix metalloproteinase-9 (MMP-9) in Fragile X Syndrome, a common genetic cause of autism. MMP-9, a protease that cleaves ECM, is differentially regulated in a number of these disorders. Despite this, few studies have addressed the interactions between PNN expression, MMP-9 activity and neuronal excitability. In this review, we highlight the current evidence for PNN abnormalities in CNS disorders associated with altered network function and MMP-9 levels, emphasizing the need for future work targeting PNNs in pathophysiology and therapeutic treatment of neurological disorders.