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.

Keywords: PV interneurons; epilepsy; extracellular matrix; matrix metalloproteinase; perineuronal net; seizure.

Figure 1.

Perineuronal nets in the central nervous system. A, Immunohistochemical staining with fluorescently labeled WFA showing perineuronal nets in mouse cerebral cortex. Perineuronal nets surround cell body axon initial segments and dendrites (scale 10 µm). B, Schematics of the structural organization of PNN constituents on the PV neuron membrane. Long chains of HAS-associated HA are connected to the lecticans aggrecan, neurocan, brevican, and versican via link proteins. This multimolecular complex is further strengthened by tenascins, especially TnR, which crosslink lecticans, link proteins and HA to give rise to a lattice-like appearance. The sulfated proteoglycans turn PNNs into a sphere with a high density of stationary negative charges, which, in combination with the polarized groups of proteoglycans maintain ionic homeostasis and hydration capacity. HA indicates hyaluronic acid/hyaluronan; HAS, hyaluronic acid synthase; PNNs, perineuronal nets; PV, parvalbumin; TnR, tenascin-R; WFA, Wisteria floribunda agglutinin.

Figure 2.

Function of PNNs in physiology and epilepsy. A, In normal physiological conditions, PNNs around the PV interneurons decrease their membrane capacitance (a1), allowing them to generate a high spike frequency (a2) to release sufficient GABA (a3) to balance the excitatory drive (a4). Intact high-density negative charges on ECM and PNNs also maintain a low intracellular Cl⁻ concentration in the principal neurons (a5) retaining a hyperpolarization effect of GABA (a6). A delicate balance of MMPs and TIMPs maintain the normal density and architecture of the PNNs (a7). Intact PNNs also interact with extracellular cations including calcium ions. B, Epileptogenic insults such as traumatic brain injury, glioma, stroke, and so on decrease TIMPs and increase the extracellular MMPs and ADAMTs that cleave the PNNs (b1) and consequently increase capacitance (b2), decrease spiking ability (b3), and reduce GABA release (b4). Prolonged deficiency of GABA release from PV neurons gradually builds-up the excitatory drive (b5) to generate hyperactivity. ECM disruption also alters the Cl⁻ homeostasis in principal neurons (b6) causing GABA to depolarize (b7) them and increase excitatory drive (b5). Reactive astrocytes after epileptogenic insults secrete proteoglycans and extracellular proteases, causing ECM and PNN remodeling (b8). ADAMTs indicate a disintegrin and metalloproteinase with thrombospondin motifs; ECM, extracellular matrix; MMPs, matrix metalloproteinases; PNNs, perineuronal nets; PV, parvalbumin; TIMPs, tissue inhibitors of metalloproteinases.