GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor‐associated epilepsy

摘要: Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution GABAergic disinhibition disease pathophysiology. In validated mouse glioma model, we found that parvalbumin-positive inhibitory interneurons are significantly reduced, corresponding with deficits spontaneous evoked neurotransmission. Most remaining neurons exhibit elevated intracellular Cl(-) concentration ([Cl(-) ]i ) consequently depolarizing, gamma-aminobutyric acid (GABA) responses. these neurons, plasmalemmal expression KCC2, which establishes low [Cl(-) required for GABAA R-mediated inhibition, is decreased. Interestingly, reductions inhibition independent Glu release, but presence both decreased SXC suggest renders neuronal networks hyper-excitable susceptible seizures triggered stimuli, propose KCC2 as therapeutic target.