The Expanding Therapeutic Potential of Neuronal KCC2

Abstract

Dysfunctions in GABAergic inhibitory neural transmission occur in neuronal injuries and neurological disorders. The potassium–chloride cotransporter 2 (KCC2, SLC12A5) is a key modulator of inhibitory GABAergic inputs in healthy adult neurons, as its chloride (Cl−) extruding activity underlies the hyperpolarizing reversal potential for GABAA receptor Cl− currents (EGABA). Manipulation of KCC2 levels or activity improve symptoms associated with epilepsy and neuropathy. Recent works have now indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in an injured mouse’s spinal cord, leading to functional recovery and the attenuation of neuronal abnormality and disease phenotype associated with a mouse model of Rett syndrome (RTT). KCC2 interacts with Huntingtin and is downregulated in Huntington’s disease (HD), which contributed to GABAergic excitation and memory deficits in the R6/2 mouse HD model. Here, these recent advances are highlighted, which attest to KCC2’s growing potential as a therapeutic target for neuropathological conditions resulting from dysfunctional inhibitory input.

The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities

“…This extensive study revealed the mechanisms involved in NKCC1 molecular transportation and communication and further provided insights into ion selectivity as well as coupling and translocation; a clearer framework for understanding the physiological functions of NKCC1 in relation to human diseases was also established [57]. Besides, modulation of NKCC1 activity alongside that of KCC2 has been implicated in the development and progression of HD [2,[58][59][60]. These CCCs are differentially expressed over the course of development, and so the activity of KCC2 and NKCC1 is not synonymous between immature and mature neurons [50].…”

“…Noteworthily, recent works have now potentially indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in injured mouse and patient brain, leading to functional recovery and the amelioration of neuronal abnormality and disease phenotype associated with mouse and human models of neurological disorders including HD [58][59][60]86,88,89]. Indeed, there is a growing potential for KCC2 as a vital therapeutic target for neurological diseases and subsequent inhibitory input dysfunctions [60].…”

“…Not only is KCC2 expression altered in HD, but NKCC1 expression is also abnormally increased [2,58,60]. In fact, there are several reports alluding that enhanced NKCC1 activity may contribute to the pathogenesis of HD [2,[58][59][60]. In a recent mice and human study, Hsu and co-workers [58] demonstrated that NKCC1 mRNA expression increased in the striatum of R6/2 and Hdh 150Q/7Q transgenic HD mice and caudate nucleus of HD patients.…”

“…Importantly, the inhibition/stimulation of KCC2/NKCC1 pair via protein phosphorylation is through a regulatory mechanism that works in a reciprocal pattern [53,64] and members of the with-no-lysine kinase (WNKs) family as well as their downstream targets; STE20/SPS1-related proline/alanine rich kinase (SPAK) and oxidative stress response kinase (OSR1) are the most prominent kinases that regulate this process [52,[64][65][66][67]. Consequently, impaired ion homeostasis resulting from mutation in the physiological function of some of this transporter pair and/or their upstream regulators may be detrimental and subsequently result in diminished inhibition and augmented network hyperexcitability, which underlies numerous neurological disorders [52,66,[68][69][70][71] including HD [58][59][60].…”

“…When [Cl − ] i exceeds equilibrium, depolarisation events contribute to the onset of neurological disease [35,46]. Decreased KCC2 expression coupled with increased NKCC1 expression and/or activity has been documented in several pathologies [63,68,69,71], including HD [58][59][60]. In HD, HTT is mutated (mHTT) and acts to alter KCC2 and NKCC1 expressions and activity [58,59] through mechanisms that remain undetermined.…”