GABAergic Disinhibition and Impaired KCC2 Cotransporter Activity Underlie Tumor-Associated Epilepsy

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 GABA(A)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. GLIA 2015;63:23-36 Main Points In a mouse model of glioma peritumoral epilepsy, we show that peritumoral cortex contained fewer PV-positive GABAergic interneurons and elevated [Cl-](i) leading to depolarizing GABA responses and reduced inhibition in peritumoral neurons.