title: Perineuronal net degradation in epilepsy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Stanford University School of Medicine, Palo Alto, California, U.S.A.
authors.forename: Elyse K
authors.identifier: http://orcid.org/0000-0002-0675-6955
authors.initials: EK
authors.lastname: Rankin-Gee
authors.affiliation: Department of Neurology, The Children's Hospital of Philadelphia, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Paulette A
authors.initials: PA
authors.lastname: McRae
authors.affiliation: Department of Neurology, The Children's Hospital of Philadelphia, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Esther
authors.initials: E
authors.lastname: Baranov
authors.affiliation: Department of Neurology, The Children's Hospital of Philadelphia, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rogers
authors.affiliation: Department of Neurology, The Children's Hospital of Philadelphia, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Luke
authors.initials: L
authors.lastname: Wandrey
authors.affiliation: Department of Neurology, Stanford University School of Medicine, Palo Alto, California, U.S.A.|Department of Neurology, The Children's Hospital of Philadelphia, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, U.S.A.
authors.forename: Brenda E
authors.initials: BE
authors.lastname: Porter
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D009415:Nerve Net / Q000187:drug effects / Q000473:pathology*; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology*; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*
chemical_list: D010862:Pilocarpine
keywords: Aggrecan; Epilepsy; Matrix metalloproteinase; Perineuronal net; Seizure; Status epilepticus