Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability.

INTRODUCTION: Epilepsy is a common neurological disorder of neuronal hyperexcitability that begets recurrent and unprovoked seizures. The lack of a truly satisfactory pharmacotherapy for epilepsy highlights the clinical urgency for the discovery of new drug targets. To that end, targeting the electroneutral K+/Cl- cotransporter KCC2 has emerged as a novel therapeutic strategy for the treatment of epilepsy. AREAS COVERED: We summarize the roles of KCC2 in the maintenance of synaptic inhibition and the evidence linking KCC2 dysfunction to epileptogenesis. We also discuss preclinical proof-of-principle studies that demonstrate that augmentation of KCC2 function can reduce seizure activity. Moreover, potential strategies to modulate KCC2 activity for therapeutic benefit are highlighted. EXPERT OPINION: Although KCC2 is a promising drug target, questions remain before clinical translation. It is unclear whether increasing KCC2 activity can reverse epileptogenesis, the ultimate curative goal for epilepsy therapy that extends beyond seizure reduction. Furthermore, the potential adverse effects associated with increased KCC2 function have not been studied. Continued investigations into the neurobiology of KCC2 will help to translate promising preclinical insights into viable therapeutic avenues that leverage fundamental properties of KCC2 to treat medically intractable epilepsy and other disorders of failed synaptic inhibition with attendant neuronal hyperexcitability.