Abstract
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.
Highlights
First described by Golgi and Cajal (Golgi, 1893; Ramón and Cajal, 1897), Perineuronal nets (PNN) are assemblies of extracellular matrix (ECM) proteins, which form net-like structures around neurons (Brauer et al, 1982, 1984)
While PNNs were first identified in the late 1800s, much of our current knowledge about PNN structure and function can be attributed to a renewed interest in PNNs almost a Abbreviations: AD, Alzheimer’s disease; ADAMTs, a disintegrin and metalloproteinase with thrombospondin motif; chABC, chondroitinase ABC; CNS, central nervous system; CSPG, chondroitin sulfate proteoglycan; E, embryonic; E/I, excitatory/inhibitory; ECM, extracellular matrix; EEG, electroencephalography; Fragile X syndrome (FXS), Fragile X Syndrome; GAD, glutamate decarboxylase; GAG, glycosaminoglycan; GCL, glutamate cysteine ligase; GSH, glutathione; HAS, hyaluronan synthase; MMP-9, matrix metalloproteinase-9; NGF, nerve growth factor; Otx2, orthodenticle homeoprotein 2; P, postnatal; PNN, perineuronal net; PV, parvalbumin; TIMPs, tissue inhibitor of MMPs; WFA, wisteria floribunda agglutinin
Using this hypothesis as a scaffold, we bring together evidence from studies of schizophrenia, AD, and epilepsy to suggest that systematic studies of the interplay between MMP-9, PNN and PV cells may be key to understanding mechanisms of multiple CNS disorders at the cellular and circuit levels
Summary
First described by Golgi and Cajal (Golgi, 1893; Ramón and Cajal, 1897), PNNs are assemblies of ECM proteins, which form net-like structures around neurons (Brauer et al, 1982, 1984). Tenascins, and hyaluronan are expressed during embryonic development, the classic net-like structure of PNNs is not typically seen until later during postnatal development It is unclear how these molecules are assembled to form PNN around neurons, but some studies suggest that both neurons and glial cells are involved in the process (Miyata et al, 2007; Pyka et al, 2011). Monocular deprivation followed by light exposure in adult mice was associated with reduced WFA-expressing PNNs, lower aggrecan levels, and increased MMP-9 activity, as well as reduced PV cell output, increased firing of regular-spiking cells, and reduced gamma power (Murase et al, 2017)
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