Perineuronal net degradation in epilepsy
Abstract
Summary: 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 (MMP s) 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(Ch ABC) 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.
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Perineuronal net loss is reported in seizure and prion disease.
“PNN loss is also reported in other neurological disorders such as seizure [34] and prion disease [35]”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [34]
Degrading PNNs using ChABC decreases the threshold for PTZ-induced myoclonic seizures.
“Moreover, consistent with our own findings, degrading PNNs using ChABC decreases the threshold for PTZ-induced myoclonic seizures44.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [44]
Aggrecan has been previously identified as an MMP-9 target.
“As aggrecan has been previously identified as an MMP-9 target (Mercuri et al., 2000; Madsen et al., 2010; Rankin-Gee et al., 2015), aggrecan-rich PNNs may be unstable in the presence of MMP-9, leading to abnormal development and neural excitability (Murase et al., 2017; Wen et al., 2017).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Rankin-Gee et al., 2015
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- Authors
- Rankin‐Gee, E. K., McRae, P. A., Baranov, E., Rogers, S., Wandrey, L., & Porter, B. E.
- Affiliations
- Department of Neurology Stanford University School of Medicine Palo Alto California U.S.A
- Children's Hospital of Philadelphia (US)
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2015-05-29
- Volume
- 56
- Issue
- 7
- Pages
- 1124-1133
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- OpenAlex
- W2107420159
- Cited by
- 100
- References
- 11
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 11 · 2021: 12 · 2020: 9 · 2019: 14 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 2
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS56222, Cure Take Flight Award)
- National Institutes of Health (NSR01NS056222)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- perineuronal nets, status epilepticus, epilepsy, matrix metalloproteinases, parvalbumin interneurons, hippocampus, chondroitinase ABC, pilocarpine-induced epilepsy, pentylenetetrazole-induced seizures, seizure susceptibility, myoclonic seizures
- MeSH terms
- Animals, Hippocampus, Male, Nerve Net, Oligodendroglia, Pilocarpine, Status Epilepticus, Rats, Sprague-Dawley, Mice, Rats
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