Role of NKCC1 and KCC2 in Epilepsy: From Expression to Function

Abstract

As a main inhibitory neurotransmitter in the central nervous system, γ-aminobutyric acid (GABA) activates chloride-permeable GABAa receptors (GABAa Rs) and induces chloride ion (Cl^-) flow, which relies on the intracellular chloride concentration ([Cl^-]_i) of the postsynaptic neuron. The Na-K-2Cl cotransporter isoform 1 (NKCC1) and the K-Cl cotransporter isoform 2 (KCC2) are two main cation-chloride cotransporters (CCCs) that have been implicated in human epilepsy. NKCC1 and KCC2 reset [Cl^-]_i by accumulating and extruding Cl^-, respectively. Previous studies have shown that the profile of NKCC1 and KCC2 in neonatal neurons may reappear in mature neurons under some pathophysiological conditions, such as epilepsy. Although increasing studies focusing on the expression of NKCC1 and KCC2 have suggested that impaired chloride plasticity may be closely related to epilepsy, additional neuroelectrophysiological research aimed at studying the functions of NKCC1 and KCC2 are needed to understand the exact mechanism by which they induce epileptogenesis. In this review, we aim to briefly summarize the current researches surrounding the expression and function of NKCC1 and KCC2 in epileptogenesis and its implications on the treatment of epilepsy. We will also explore the potential for NKCC1 and KCC2 to be therapeutic targets for the development of novel antiepileptic drugs.

Keywords: KCC2; NKCC1; bumetanide; electrophysiology; epilepsy.

Figure 1

(A) Chloride concentration regulatory mechanisms underlying GABAa receptor-mediated responses in immature and mature CNS neurons. (Left): Upregulated NKCC1 is the main regulator which mediates Cl⁻ uptake in immature CNS neurons in parallel with downregulated KCC2 or in its absence. (Right): KCC2 is the principal K-Cl cotransporter in parallel with subsequent downregulated NKCC1 in mature CNS neurons. Cl⁻ transported by NKCC1 and KCC2 is facilitated by an electrochemical gradient of Na⁺ and K⁺ created by the Na⁺/K⁺-ATPase. The relative activity of NKCC1 and KCC2 and their opposing effects on [Cl⁻]_i determines the value of E_Cl− relative to the membrane potential (V_m). GABA binds to corresponding GABAa receptors and opens ligand-gated Cl⁻ channels which are also permeable to HCO₃⁻. Expression profiles of NKCC1 and KCC2 varies at different developmental stages. In several pathophysiologic conditions, such as epilepsy, neurons experience “recapitulation” and dedifferentiation to some key and special stages of early neuronal development. (B) Molecular cascades leading to expressive and functional abnormalities in NKCC1 and KCC2. Expression levels of NKCC1 and KCC2 mRNA ①, protein levels ②, and designated regulatory pathways ③ have been shown to be altered. Summarized findings are from animal models as well as human studies.