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Increased neuronal plasticity and neuronal cell loss has been implicated in the development of epilepsy following injury. Parvalbumin fast spiking inhibitory interneurons have a robust extracellular matrix coating their cell bodies and the proximal dendrites called the perineuronal net (PNN). The role of the PNN is not clear but it has been implicated in closing of the critical period, altering seizure thresholds and providing neuronal protection from oxidative stress. The PNN is susceptible to degradation following a prolonged seizure and there is an increase in proteolytic-fragments of the PNN enriched proteoglycan aggrecan (Dzwonek et al., 2004). Here we demonstrate an increase in matrix metalloproteinase (MMP) activity in the hippocampus following status epilepticus (SE). We further assessed MMP3 and 13, two of 24 identified MMPs, both MMP3 and 13 mRNA increase in the hippocampus after SE and MMP13 activity increases by functional assay as well as it co-localizes with PNN in rat brain. In contrast, two of the brain expressed ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) also implicated in aggrecan degradation, did not consistently increase following SE though ADAMTS4 is highly expressed in glia and ADAMTS5 in neuronal cell bodies and their processes. The increase in MMP activity following SE suggests that in the future studies, MMP inhibitors are candidates for blocking PNN degradation and assessing the role of the PNN loss in epileptogenesis and cellular function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: We previously reported loss of perineuronal net (PN) immunohistochemical staining around parvalbumin-positive interneurons in the hippocampus of rats after an episode of status epilepticus (SE). We hypothesized that the loss of the PN could alter seizure susceptibility and that matrix metalloproteinases (MMPs) were candidates for degradation of the PN following SE., Methods: The pilocarpine chemoconvulsant rodent epilepsy model was used to characterize the degradation of the aggrecan component of the PN in the hippocampus following SE. Chondroitinase ABC (ChABC) was used to degrade the PN in mice. Onset, number, and duration of pentylenetetrazole (PTZ)-induced seizures were assessed., Results: The loss of the PN in the hippocampus following SE is at least partially related to degradation of the aggrecan PN component by MMP activity. Forty-eight hours after SE, a neoepitope created by MMP cleavage of aggrecan was present and concentrated around parvalbumin-positive interneurons. The increase in aggrecan cleavage products was found at 48 h, 1 week, and 2 months after SE, with different fragments predominating over time. We demonstrate ongoing aggrecan proteolysis and fragment accumulation in the hippocampus of adult control rats, as well as in SE-treated animals. Degradation of the PN alters the seizure response to PTZ. ChABC treatment caused an increase in myoclonic seizures following PTZ administration, a delayed onset of Racine stage 4/5 seizure, and a decreased duration of Racine stage 4/5 seizure., Significance: Status epilepticus increases MMP proteolysis of aggrecan, pointing to MMP activity as one mechanism of PN degradation post-SE. There is accumulation of aggrecan fragments in adult rat hippocampus of both control and SE-exposed animals. Loss of the PN was associated with increased numbers of myoclonic seizures; it also, delayed and shortened the duration of Racine stage 4/5 seizures, suggesting a complex relationship between the PN and seizure susceptibility., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

In the rodent model of temporal lobe epilepsy, there is extensive synaptic reorganization within the hippocampus following a single prolonged seizure event, after which animals eventually develop epilepsy. The perineuronal net (PN), a component of the neural extracellular matrix (ECM), primarily surrounds inhibitory interneurons and, under normal conditions, restricts synaptic reorganization. The objective of the current study was to explore the effects of status epilepticus (SE) on PNs in the adult hippocampus. The aggrecan component of the PN was studied, acutely (48 h post-SE), sub-acutely (1 week post-SE) and during the chronic period (2 months post-SE). Aggrecan expressing PNs decreased by 1 week, likely contributing to a permissive environment for neuronal reorganization, and remained attenuated at 2 months. The SE-exposed hippocampus showed many PNs with poor structural integrity, a condition rarely seen in controls. Additionally, the decrease in the aggrecan component of the PN was preceded by a decrease in hyaluronan and proteoglycan link protein 1 (HAPLN1) and hyaluronan synthase 3 (HAS3), which are components of the PN known to stabilize the connection between aggrecan and hyaluronan, a major constituent of the ECM. These results were replicated in vitro with the addition of excess KCl to hippocampal cultures. Enhanced neuronal activity caused a decrease in aggrecan, HAPLN1 and HAS3 around hippocampal cells in vivo and in vitro, leaving inhibitory interneurons susceptible to increased synaptic reorganization. These studies are the foundation for future experiments to explore how loss of the PN following SE contributes to the development of epilepsy., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)