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GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy: Reduced KCC2 Underlie Tumor-Related Epilepsy
Open accessAbstract
Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by the cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution of GABAergic disinhibition to disease pathophysiology. In a validated mouse glioma model, we found that peritumoral parvalbumin-positive GABAergic inhibitory interneurons are significantly reduced, corresponding with deficits in spontaneous and evoked inhibitory neurotransmission. Most remaining peritumoral neurons exhibit elevated intracellular Cl(-) concentration ([Cl(-) ]i ) and consequently depolarizing, excitatory gamma-aminobutyric acid (GABA) responses. In these neurons, the plasmalemmal expression of KCC2, which establishes the low [Cl(-) ]i required for GABAA R-mediated inhibition, is significantly decreased. Interestingly, reductions in inhibition are independent of Glu release, but the presence of both decreased inhibition and decreased SXC expression is required for epileptogenesis. We suggest GABAergic disinhibition renders peritumoral neuronal networks hyper-excitable and susceptible to seizures triggered by excitatory stimuli, and propose KCC2 as a therapeutic target.
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“The cellular and molecular changes underlying tumor-associated epilepsy collectively point to a decrease in GABAergic and increase in glutamatergic transmission as the major contributors3–6.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
In the citing paper
“the peritumoral brain shows ~35% reduction in the density of fast spiking GABAergic interneurons3”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
In the citing paper
“the remaining GABAergic neurons show a significantly reduced inhibitory potential.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
In the citing paper
“Glu release, while necessary, is insufficient to drive peritumoral epilepsy3. Rather an additional loss of GABAergic inhibition is required”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
In the citing paper
“Seizures originate from the PTC, and previous studies3,5,6 show altered excitation−inhibition balance in the PTC due to changes in glutamatergic and GABAergic activity.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
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Metadata
- Authors
- Campbell, S. L., Robel, S., Cuddapah, V. A., Robert, S., Buckingham, S. C., Kahle, K. T., & Sontheimer, H.
- Affiliations
- University of Alabama at Birmingham (US)
- Boston Children's Hospital (US)
- Corresponding author
- Sontheimer, Harald
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2014-07-26
- Volume
- 63
- Issue
- 1
- Pages
- 23-36
- ISSN
- 0894-1491 (ISSN-L)
- PMC
- PMC4237714
- OpenAlex
- W1562543772
- Cited by
- 185
- References
- 53
- Citations by year
- 2026: 21 · 2025: 32 · 2024: 18 · 2023: 28 · 2022: 14 · 2021: 6 · 2020: 16 · 2019: 12 · 2018: 10 · 2017: 9 · 2016: 11 · 2015: 8
- FWCI
- 7.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5R01-NS036692, 2R01-NS052634, 5T32NS048039-03)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Keywords
- tumor-associated epilepsy, glioma, GABAergic disinhibition, parvalbumin interneurons, intracellular chloride, GABAergic inhibition, SLC7A11, glutamate release, epileptogenesis, GABAA receptor, therapeutic target
- MeSH terms
- K Cl- Cotransporters, Animals, Brain Neoplasms, Epilepsy, Female, gamma-Aminobutyric Acid, Glioma, Interneurons, Male, Synaptic Transmission, Neurons, Receptors, GABA-A, Symporters, Mice
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