KCC2, epileptiform synchronization, and epileptic disorders

The K⁺-Cl^- co-transporter KCC2 is a neuron-specific, Cl^- extruder that uses K⁺ gradient for maintaining low intracellular [Cl^-]. It is indeed well established that sustaining an outwardly-directed electrochemical Cl^- gradient across the neuronal membrane is fundamental for a proper function of postsynaptic GABA_A receptor signaling. In particular, studies in the last two decades have shown that KCC2 activity is important to maintain a hyperpolarizing GABAergic neurotransmission. Conversely, low KCC2 activity should lead to depolarizing, and under specific conditions, excitatory GABAergic transmission. Not surprisingly given the critical role of KCC2 in regulating the inhibitory drive, alterations in its expression levels and activity are linked with epilepsy. Here, we will first summarize data regarding the role of KCC2 in epileptiform synchronization. Next, we will review evidence indicating that KCC2 expression and function are altered in chronic epileptic disorders, both in the developing and adult brain. We will also go through recent findings regarding the molecular mechanisms underlying the changes in KCC2 activity that occur following seizures. Finally, we will consider the modulation of KCC2 function as a potential, novel therapeutic target for the treatment of epileptic disorders.