Molecular Mechanisms of Epilepsy: The Role of the Chloride Transporter KCC2

Abstract

Epilepsy is a neurological disease characterized by abnormal or synchronous brain activity causing seizures, which may produce convulsions, minor physical signs, or a combination of symptoms. These disorders affect approximately 65 million people worldwide, from all ages and genders. Seizures apart, epileptic patients present a high risk to develop neuropsychological comorbidities such as cognitive deficits, emotional disturbance, and psychiatric disorders, which severely impair quality of life. Currently, the treatment for epilepsy includes the administration of drugs or surgery, but about 30% of the patients treated with antiepileptic drugs develop time-dependent pharmacoresistence. Therefore, further investigation about epilepsy and its causes is needed to find new pharmacological targets and innovative therapeutic strategies. Pharmacoresistance is associated to changes in neuronal plasticity and alterations of GABA_A receptor-mediated neurotransmission. The downregulation of GABA inhibitory activity may arise from a positive shift in GABA_A receptor reversal potential, due to an alteration in chloride homeostasis. In this paper, we review the contribution of K⁺-Cl⁻-cotransporter (KCC2) to the alterations in the Cl^– gradient observed in epileptic condition, and how these alterations are coupled to the increase in the excitability.