Perineuronal Net Dynamics in the Pathophysiology of Epilepsy

Abstract

Perineuronal nets (PNNs) are condensed extracellular matrix (ECM) assemblies of polyanionic chondroitin sulfate proteoglycans, hyaluronan, and tenascins that primarily wrap around GABAergic parvalbumin (PV) interneurons. During development, PNN formation terminates the critical period of neuroplasticity, a process that can be reversed by experimental disruption of PNNs. Perineuronal nets also regulate the intrinsic properties of the enclosed PV neurons thereby maintaining their inhibitory activity. Recent studies have implicated PNNs in central nervous system diseases as well as PV neuron dysfunction; consequently, they have further been associated with altered inhibition, particularly in the genesis of epilepsy. A wide range of seizure presentations in human and rodent models exhibit ECM remodeling with PNN disruption due to elevated protease activity. Inhibition of PNN proteolysis reduces seizure activity suggesting that PNN degrading enzymes may be potential novel therapeutic targets.

Brevican and Neurocan Cleavage Products in the Cerebrospinal Fluid - Differential Occurrence in ALS, Epilepsy and Small Vessel Disease

“…Under aging and pathophysiological conditions the integrity and composition of the brain ECM undergo extensive changes, leading to a disturbed equilibrium of ECM production and deposition on one hand and ECM cleavage and clearance on the other hand ( Ulbrich et al, 2021 ). In human epilepsy as well as in rodent epilepsy models manifold ECM remodeling phenotypes have been reported in the brain tissue, with a particular focus on PNN disruption due to increased proteolysis, which may contribute to epileptogenesis (summarized in Dityatev et al (2010) , Chaunsali et al (2021) ). In histochemical analyses of postsurgical specimen from focal cortical dysplasia patients, known for a longstanding epilepsy with a high seizure burden, a complete reorganization of the ECM was reported with reduced brevican expression and disturbance of extracellular space diffusion parameters ( Zamecnik et al, 2012 ).…”

Region-Specific Alterations of Perineuronal Net Expression in Postmortem Autism Brain Tissue

“…One study measured PNN degradation and found that seizures lead to shifts in expression of PNN components, including HPLN1 ( Mcrae et al, 2012 ), which may be due to release of matrix metalloproteinases following status epilepticus ( Dzwonek et al, 2004 ; Dubey et al, 2017 ). However, a human postmortem study of PNN degradation after epilepsy did not show dysregulation of PNNs ( Rogers et al, 2018 ), which may be dependent on the PNN markers examined and timing following seizures (reviewed in Chaunsali et al, 2021 ). Consequently, it is not clear whether PNNs degrade similarly in humans or whether the degradation is transient and potentially stabilizes over time.…”

Disruption of KCC2 in Parvalbumin-Positive Interneurons Is Associated With a Decreased Seizure Threshold and a Progressive Loss of Parvalbumin-Positive Interneurons

“…Many PV-INs are ensheathed by perineuronal nets (PNN) (Wen et al, 2018;Carceller et al, 2020; Figure 6A), extracellular matrix (ECM) assemblies that can be easily detected by lectins such as the Wisteria floribunda agglutinin (WFA). PNNs regulate the intrinsic properties of the encapsulated neurons and thus aid the fast-spiking of PV-INs (Chaunsali et al, 2021). The loss of PNNs has been associated with diseases such as Alzheimer (Crapser et al, 2020) and epilepsy (Tewari et al, 2018;Chaunsali et al, 2021).…”

“…PNNs regulate the intrinsic properties of the encapsulated neurons and thus aid the fast-spiking of PV-INs (Chaunsali et al, 2021). The loss of PNNs has been associated with diseases such as Alzheimer (Crapser et al, 2020) and epilepsy (Tewari et al, 2018;Chaunsali et al, 2021). Notably, WFA signals per area were drastically decreased in the hippocampus and in the somatosensory and retrosplenial cortex of 23-week-old KCC2 KO PV mice (Figure 6B).…”