GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy.
Publication/Presentation Date
1-1-2015
Abstract
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.
Volume
63
Issue
1
First Page
23
Last Page
36
ISSN
1098-1136
Published In/Presented At
Campbell, S. L., Robel, S., Cuddapah, V. A., Robert, S., Buckingham, S. C., Kahle, K. T., & Sontheimer, H. (2015). GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy. Glia, 63(1), 23–36. https://doi.org/10.1002/glia.22730
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
25066727
Department(s)
Administration and Leadership
Document Type
Article