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.
Highlights
Inhibitory neural transmission in the adult nervous system is mediated by γ-aminobutyric acid (GABA) [1] and glycine, with fast synaptic inhibition occurring largely through the ionotropic GABAA receptor (GABAA R) [2,3]
The developmental switch of GABAA R transmission towards a hyperpolarizing, inhibitory response is due primarily to changes mediated by neuronal sodium-potassium–chloride cotransporter 1 (NKCC1, mediating Cl− influx) [5] and the potassium–chloride cotransporter 2 (KCC2, mediating Cl− efflux), in particular, an enhanced KCC2 surface expression and function shortly after birth [6]
KCC2, encoded by SLC12A5, is a member of the solute carrier 12 (SLC12) family [7] that is highly expressed in neurons [8,9]
Summary
Inhibitory neural transmission in the adult nervous system is mediated by γ-aminobutyric acid (GABA) [1] and glycine, with fast synaptic inhibition occurring largely through the ionotropic GABAA receptor (GABAA R) [2,3]. Recent work with mice knock-ins of KCC2-T906A/T1007A showed that the non-phosphorylatable double mutations increased basal neuronal Cl− extrusion and limit drug-induced epileptic activity [21]. Both the S940A and the T906A/T1007A knock-ins have long-term abnormalities in terms of social behavior and cognitive function [22]. Several recent reports have further revealed KCC2’s potential as a therapeutic target beyond that of epileptic seizure and neuropathic pain These include functional recovery from spinal cord injury [45] and amelioration of disease phenotypes of Rett Syndrome [46]. The focus is on recent advances that attest to KCC2’s growing potential as a therapeutic target, and KCC2 expression or activity enhancement as a therapeutic strategy
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