title: GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy.
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.
authors: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors: Susan L
authors: SL
authors: Campbell
authors: Stefanie
authors: S
authors: Robel
authors: Vishnu A
authors: VA
authors: Cuddapah
authors: Stephanie
authors: S
authors: Robert
authors: Susan C
authors: SC
authors: Buckingham
authors: Kristopher T
authors: KT
authors: Kahle
authors: Harald
authors: H
authors: Sontheimer
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000150:complications / Q000378:metabolism*; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000150:complications / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D011963:Receptors, GABA-A; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters
keywords: GABA; KCC2; glioma; peritumoral epilepsy