Abnormal KCC2 expression and function in a mouse model of epilepsy and tuberous sclerosis complex

Objective Drug‐resistant epilepsy is a common, severe manifestation of the genetic disorder tuberous sclerosis complex (TSC). Although significant mechanistic and therapeutic advances have been made in TSC, treatments for seizures remain largely ineffective. Decreased expression of the potassium–chloride cotransporter KCC2 is associated with depolarizing γ‐aminobutyric acid (GABA) signaling and increased neuronal excitability in the immature brain and in certain pathological states. In this study, we investigated abnormalities in KCC2 expression and function in a mouse model of TSC‐related epilepsy. Methods Tsc1 GFAP CKO mice were used to investigate KCC2 expression by Western blotting and immunohistochemistry. The effects of KCC2 pharmacological modulators on KCC2 expression and seizures in Tsc1 GFAP CKO mice were tested by Western blotting and video‐electroencephalography. Results KCC2 expression was decreased in Tsc1 GFAP CKO mice compared with controls, including prior to the onset of seizures. The decrease in KCC2 expression was reversed by the mTOR inhibitor rapamycin as well as select KCC2 modulators. These KCC2 modulators also decreased seizures in Tsc1 GFAP CKO mice. Significance Decreased KCC2 expression may lead to impaired GABAergic inhibition and increased neuronal excitability, contributing to epileptogenesis in TSC. Potentiation of KCC2 expression may represent a novel, effective therapeutic approach for epilepsy in TSC.