Seizing Control of KCC2: A New Therapeutic Target for Epilepsy

Deficits in GABAergic inhibition result in the abnormal neuronal activation and synchronization that underlies seizures. However, the molecular mechanisms responsible for transforming a normal brain into an epileptic one remain largely unknown. Hyperpolarizing inhibition mediated by type A GABA (GABAA) receptors is dependent on chloride extrusion by the neuron-specific type 2K+–Cl− cotransporter (KCC2). Loss-of-function mutations in KCC2 are a known cause of infantile epilepsy in humans and KCC2 dysfunction is present in patients with both idiopathic and acquired epilepsy. Here we discuss the growing evidence that KCC2 dysfunction has a central role in the development and severity of the epilepsies. Phosphoregulation supersedes the classic ways of thinking about transporters (total and surface numbers). Type 2K+–Cl− cotransporter (KCC2) loss-of-function mutations cause infantile epilepsy. Idiopathic and acquired epilepsy both involve downregulation of KCC2. KCC2 is dysfunctional in neurodevelopmental disorders that are associated with seizures.