Perineuronal net degradation in epilepsy

Abstract

SUMMARYObjective: 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.

Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice

“…AS mice with the capacity for conditional reinstatement of maternal Ube3a gyrus is a reliable anatomical correlate of enhanced epileptogenesis in flurothyl-kindled AS mice. Converging lines of evidence show that seizures can alter components of PNNs, but the specific proteins involved, and the direction and duration of changes may vary depending on a number of factors -the age of the animal, the seizure induction method, the brain region studied, and the time elapsed following seizure (27)(28)(29)(30). Each of these factors, and hence the nature of the relationship between abnormal PNN deposition and epileptogenesis in AS model mice, remains to be rigorously investigated.…”

“…We next questioned whether gross changes in the hippocampal extracellular matrix, perineuronal nets (PNNs) in particular, might associate with the exaggerated epileptogenesis phenotype in flurothyl-kindled AS model mice. PNNs are uniquely localized around specific neurons to regulate synapse stability and plasticity in the adult CNS (26), and have been associated with epileptic activity during early and late development (27)(28)(29)(30). To examine a possible link between changes in PNNs and enhanced epileptogenesis in AS model mice, we labeled PNNs with biotinylated Wisteria floribunda agglutinin (WFA) in flurothyl-kindled mice before (Supplemental Figure 3), or 1 hour after (Figure 4, A and B), retest.…”

Effects of Huazhuo Jiedu Shugan Decoction on Cognitive and Emotional Disorders in a Rat Model of Epilepsy: Possible Involvement of AC-cAMP-CREB Signaling and NPY Expression

“…It is mainly responsible for the storage, conversion, and orientation of long-term memory, and it has important roles in information processing. Repeated convulsions in rodents have far-reaching and harmful effects on hippocampal long-term memory, which can reduce the plasticity of hippocampal information processing [38]. Hippocampus is the best area to observe the pharmacodynamic changes in cognitive and emotional disorders caused by epileptic injury [39,40].…”

A potential role for glia‐derived extracellular matrix remodeling in postinjury epilepsy

“…Several studies have demonstrated that seizures result in changes in the components of ECM, including increases in the expression of tenascin‐C (Mercado‐Gomez et al, ) and neurocan (Okamoto et al, ) and decreases in aggrecan and HAPLN type 1 (McRae et al, ; for reviews see Dityatev and Fellin, ; McRae and Porter, ). Compromised structural integrity of PNNs has been found in the rodent brain with pilocarpine‐induced status epilepticus (McRae et al, ; Rankin‐Gee et al, ). It is noteworthy that enzymatic degradation of ECM by chondroitinase ABC lowered the threshold for myoclonic seizures after pentylenetetrazole treatment but delayed the onset and duration of Racine stage 4/5 seizure (Rankin‐Gee et al, ).…”

“…Compromised structural integrity of PNNs has been found in the rodent brain with pilocarpine‐induced status epilepticus (McRae et al, ; Rankin‐Gee et al, ). It is noteworthy that enzymatic degradation of ECM by chondroitinase ABC lowered the threshold for myoclonic seizures after pentylenetetrazole treatment but delayed the onset and duration of Racine stage 4/5 seizure (Rankin‐Gee et al, ). Furthermore, a mouse line with a constitutive knockout of tenascin‐R, one of the major components of PNNs, displayed reduced perisomatic inhibition, increased excitatory transmission, and impaired long‐term potentiation (Saghatelyan et al, ).…”