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The KCC4-ISO rescue of isotonic transport depends on neuronal Cl − A. Summary figure plotting the distribution of E Cl in neurons overexpressing KCC2-KCC4 chimeric proteins under isotonic extracellular conditions. B. Summary figure plotting the distribution of E Cl in neurons overexpressing KCC2-KCC4 chimeric proteins and loaded with 50 mM intracellular Cl − under isotonic extracellular conditions. * p < 0.05, *** p < 0.001.
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KCC2 is the neuron-specific member of the of K(+)-Cl(-) cotransporter gene family. It is also the only member of its family that is active under physiologically normal conditions, in the absence of osmotic stress. By extruding Cl(-) from the neuron under isotonic conditions, this transporter maintains a low concentration of neuronal Cl(-), which is...
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Context 1
... the results in Figures 1C, 2B, 3B and 4A, the data were normally distributed and thus we determined statistical significance by performing a one-way ANOVA with a post-hoc Tukey test. For the results in Figure 4B, we performed a Kruskal-Wallis ANOVA on Ranks with post hoc Dunn's test. Statistical significance was determined as follows: * p < 0.05, ** p < 0.01, *** p < 0.001. ...
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... conditions. We transfected cultured hippocampal neurons with a KCC2-KCC4 chimeric construct, where we introduced the KCC2 ISO domain into KCC4 (KCC4-ISO). When we made gramicidin perforated patch clamp recordings from neurons transfected with KCC4-ISO, we found that isotonic Cl − transport was not conferred (E Cl = −61.92 ± 2.83 mV, n = 12; Fig. 4A), compared to neurons transfected with KCC2 (E Cl = −97.56 ± 4.49 mV, n = 09p > 0.001). However, it is known that K + -Cl − cotransporter activity (including KCC4) is increased at higher levels of intracellular Cl − ( Gillen and Forbush, 1999, Bergeron et al., 2006, Bergeron et al., 2009), thus we asked whether increased levels of ...
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... ISO domain could in fact confer KCC4 with constitutive isotonic activity. Under these conditions of elevated neuronal Cl − , we found that KCC4 containing the ISO domain (KCC4-ISO) significantly hyperpolarized these neurons when compared to full length KCC4 (KCC4-ISO E Cl = −23.08 ± 3.96 mV, n = 14; KCC4 E Cl = 13.04 ± 2.49 mV, n = 11; p < 0.05; Fig. 4B). Moreover, the E Cl of neurons overexpressing KCC4-ISO was not significantly different from neurons overexpressing KCC2 (KCC2 E Cl = −34.17 ± 4.93 mV, n = 16; p > 0.05; Fig. 4B), indicating that the addition of the KCC2 ISO domain to KCC4 can confer KCC4 with constitutive isotonic transport when neuronal Cl − levels have been elevated ...
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... significantly hyperpolarized these neurons when compared to full length KCC4 (KCC4-ISO E Cl = −23.08 ± 3.96 mV, n = 14; KCC4 E Cl = 13.04 ± 2.49 mV, n = 11; p < 0.05; Fig. 4B). Moreover, the E Cl of neurons overexpressing KCC4-ISO was not significantly different from neurons overexpressing KCC2 (KCC2 E Cl = −34.17 ± 4.93 mV, n = 16; p > 0.05; Fig. 4B), indicating that the addition of the KCC2 ISO domain to KCC4 can confer KCC4 with constitutive isotonic transport when neuronal Cl − levels have been elevated to promote KCC4 ...
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Citations
... For instance, KCC2 possesses a poorly conserved sequence between KCCs and NKCCs at the CTD, called the ISO domain, which is required for KCC2 basal activity under isotonic conditions. The addition of the corresponding ISO domain residues (aa 1,022-1,037 in human KCC2) into the mouse KCC4 sequence turned this transporter into an active one in isotonicity (61,62). ...
The SLC12A superfamily of membrane transporters modulate the movement of cations coupled with chloride across the membrane. In doing so, these cotransporters are involved in numerous aspects of human physiology: cell volume regulation, ion homeostasis, blood pressure regulation, and neurological action potential via intracellular chloride concentration modulation. Their physiological characterization has been largely studied; however, understanding the mechanics of their function and relevance of structural domains or specific amino acids has been a pending task. In recent years, single-particle cryogenic electron microscopy (cryo-EM), has been successfully applied to members of the SLC12A family including all KCCs, NKCC1 and recently NCC; revealing structural elements that play key roles in their function. The present review analyzes the data provided by these cryo-EM reports focusing on structural domains and specific amino acids involved in ion binding, domain interactions, and other important SCL12A structural elements. Comparison of cryo-EM data from NKCC1 and KCCs is presented in the light of the two recent NCC cryo-EM studies, to propose insight into structural elements that might also be found in NCC and are necessary for its proper function. On the final sections, the importance of key coordination residues for substrate specificity and their implication on various pathophysiological conditions and genetic disorders is reviewed, as this could provide the basis to correlate structural elements with the development of novel and selective treatments, as well as mechanistic insight into the function and regulation of CCCs.
... CCCs consists of 12 transmembrane helices (TMs), flanked by intracellularly located N-and Ctermini and a large extracellular domain (ECD) (4,29,30). The termini are important for trafficking, isotonic activity, and regulation via posttranslational modifications (6,(31)(32)(33)(34)(35)(36). The Nterminal domains of KCCs have an autoinhibitory function locking the transporter in the inwardfacing state to prevent intracellular solvent access to the ion binding sites formed by residues in TM1, 3, 6, and 8 (35)(36)(37). ...
K⁺-Cl⁻ cotransporters (KCCs) play important roles in physiological processes such as inhibitory neurotransmission and cell volume regulation. KCCs exhibit significant variations in K⁺-affinities, yet recent atomic structures demonstrated that K⁺ and Cl⁻- binding sites are highly conserved, raising the question of whether additional structural elements may contribute to ion coordination. The termini and the large extracellular domain (ECD) of KCCs exhibit only low sequence identity and were already discussed as modulators of transport activity. Here, we used the extracellular loop 2 (EL2) which links transmembrane helices (TM) 3 and 4, as a mechanism to modulate ECD folding. We compared consequences of point mutations in the K⁺-binding site on the function of wild-type KCC2 (KCC2WT) and in a KCC2 variant, in which EL2 was structurally altered by insertion of an 3xHA-tag (KCC2HA). In KCC2wt, individual mutations of five residues in the K⁺-binding site resulted in a two to three-fold decreased transport rate. However, the same mutations in KCC2HA had no effect on transport activity. Homology models of mouse KCC2 with the 3xHA-tag inserted into EL2 using ab initio prediction were generated. The models suggest subtle conformational changes occur in the ECD upon EL2 modification. These data suggest that a conformational change in the ECD, e.g., by interaction with EL2, might be an elegant way to modulate the K⁺- affinity of the different isoforms in the KCC subfamily.
... The intracellular N-and Ctermini of KCC2 and NKCC1 carry regulatory sequences and phosphorylation sites. In addition, the C-terminus of KCC2 contains a motif responsible for the isotonic activity of the transporter (Acton et al., 2012;Bergeron et al., 2006;Mercado et al., 2006). KCC2 and NKCC1 Nand C-termini also participate in the regulation of membrane trafficking (Lee et al., 2010(Lee et al., , 2007Zhao et al., 2008), basolateral and apical sorting in polarized cells (Carmosino et al., 2008) and oligomerization (Casula et al., 2009(Casula et al., , 2001Parvin et al., 2007;Simard et al., 2004;Warmuth et al., 2009). ...
... In fact, the relatively high level of NKCC1 detected at adult stage is contentious with the global idea of a downregulation of NKCC1 during development (Yamada et al., 2004, reviewed by Kaila et al., 2014. In contrast to other KCCs, KCC2 is almost exclusively restricted to the CNS and is constitutively active under isotonic conditions (Acton et al., 2012;Mercado et al., 2006;Strange et al., 2000). The developmental upregulation of KCC2 expression is responsible for the early postnatal depolarizing shift in the polarity of GABAergic and glycinergic transmission in the CNS (Rivera et al., 1999). ...
... In contrast to other KCCs, KCC2 is constitutively active under isotonic conditions (Payne, 1997). A short sequence called ISO domain (1,022-1,037) located in the CTD has been shown to be responsible for this specific feature in Xenopus oocytes and hippocampal neurons (Mercado et al., 2006;Acton et al., 2012). Thus, replacement of this sequence by the corresponding KCC4 amino acids abolished constitutive KCC2 activity (Acton et al., 2012). ...
In the adult brain, synaptic inhibition is mainly mediated by the activity of GABA type A receptors (RGABAA). This inhibition depends on the electrochemical chloride gradient, which is mainly regulated by the chlorine cotransporters KCC2 and NKCC1. KCC2 transports chlorine out of the neuron, while NKCC1 is responsible for its influx. Little is known about the functions of NKCC1 in the adult brain and its regulation. Nevertheless, in pathological cases related to altered GABAergic transmission, NKCC1 is of definite functional importance, in contrast to its apparently discrete role in chlorine homeostasis. This is particularly the case in the context of epilepsy, both experimental and clinical.I have demonstrated, using single particle tracking, immunofluorescence and STORM imaging approaches, that the membrane stability of NKCC1 is rapidly regulated by lateral diffusion in an activity-dependent manner at the surface of mature hippocampal neurons. Basal glutamatergic activity regulates NKCC1 membrane dynamics in the axon but not in the somato-dendritic compartment. In the somato-dendritic compartment, NKCC1 is regulated by RGABAA-mediated signalling. I also assessed the relevance of inhibition of this pathway in the context of ictogenesis. I used a PTZ-induced ictogenesis test in SPAK243A/243A mice, which express a non-active form of SPAK. Behavioural indicators (Racine scale) and electrocorticograms showed that the effects of the mutation on these variables were mild.
... In contrast to other KCCs, KCC2 is constitutively active under isotonic conditions (Payne, 1997). A short sequence called ISO domain (1,022-1,037) located in the CTD has been shown to be responsible for this specific feature in Xenopus oocytes and hippocampal neurons (Mercado et al., 2006;Acton et al., 2012). Thus, replacement of this sequence by the corresponding KCC4 amino acids abolished constitutive KCC2 activity (Acton et al., 2012). ...
... A short sequence called ISO domain (1,022-1,037) located in the CTD has been shown to be responsible for this specific feature in Xenopus oocytes and hippocampal neurons (Mercado et al., 2006;Acton et al., 2012). Thus, replacement of this sequence by the corresponding KCC4 amino acids abolished constitutive KCC2 activity (Acton et al., 2012). Interestingly, KCC2 transporters lacking the ISO domain can still be activated under hypotonic conditions, indicating that two distinct domains are involved in KCC2 activation under isotonic vs. hypotonic conditions. ...
... The intracellular N-and Ctermini of KCC2 and NKCC1 carry regulatory sequences and phosphorylation sites. In addition, the C-terminus of KCC2 contains a motif responsible for the isotonic activity of the transporter (Acton et al., 2012;Bergeron et al., 2006;Mercado et al., 2006). KCC2 and NKCC1 Nand C-termini also participate in the regulation of membrane trafficking (Lee et al., , 2007Zhao et al., 2008), basolateral and apical sorting in polarized cells (Carmosino et al., 2008) and oligomerization (Casula et al., 2009(Casula et al., , 2001Parvin et al., 2007;Simard et al., 2004;Warmuth et al., 2009). ...
Neuronal inhibition is mainly mediated by GABAergic neurotransmission in the maturebrain, while in early stages of development GABAA receptor activity is excitatory.Underlying these different responses, intracellular chloride levels are regulated by theactivity of the co-transporters KCC2 and NKCC1. While KCC2-mediated chloride extrusionin mature brain has been described in many publications, NKCC1 role as a chlorideloading transporter scarcely reported. However under several pathological conditionswhere synaptic inhibition is impaired, the role of NKCC1 has been highlighted. This is thecase in epilepsy, whether from clinical epilepsy or experimental models, and isremarkable given the otherwise elusive functions of NKCC1 in the mature brain. As theregulatory pathways of NKCC1 are mainly unknown in the adult brain, we lackinformation on the underlying processes leading to its abrupt “awakening”. My PhDproject aimed to determine whether and how NKCC1 is regulated by neuronal activity.I demonstrated using quantum-based single particle tracking, immunofluorescence andSTORM imaging approaches that the membrane stability of NKCC1 is rapidly regulatedby lateral diffusion in an activity-dependent manner at the surface of maturehippocampal cultured neurons. Basal glutamatergic activity regulates the membranedynamics of NKCC1 in the axon but not in the somato-dendritic compartment indicatinga specific regulatory mechanism depending on the cell compartment. In the somatodendriticcompartment, NKCC1 is tuned by GABAAR-mediated signaling. Blocking oractivating GABAA receptors with muscimol or gabazine rapidly slow down and confinetransporters in the membrane. Transporter confinement would be consecutive to therecruitment and storage of transporters within endocytic zones. I then identified theunderlying molecular mechanism. GABAergic activity would control thediffusion/capture and clustering of NKCC1 via the chloride-sensitive WNK1 kinase andthe downstream SPAK and OSR1 kinases that would directly phosphorylate NKCC1 onkey threonine T203/T207/T212/T217/T230 phosphorylation sites. The fact that KCC2 isalso regulated in mature neurons by the WNK1/SPAK/OSR1 pathway and that this regulation has an inverse effect on the membrane stability, clustering and function ofKCC2 indicates that this pathway could be a target of interest in pathologies associatedwith an alteration of chloride homeostasis. Inhibition of the pathway would prevent theloss of KCC2 and the increase of NKCC1 at the surface of the neuron, thus preventing theabnormal rise of [Cl-]i in the pathology and the resulting adverse effects. I thus assessedthe relevance of inhibiting this kinase pathway in the context of ictogenesis. I used aPTZ-induced seizure assay in SPAK243A/243A mice, who express a non-active form ofSPAK. Behavioral indicators (Racine scale) and electrocorticograms (EcoG) showed thatthe effects of the mutation on these variables were mild, with a reduced death rate anda non-significant decrease in the duration of seizures. The moderate effect could be dueto the fact that other effector of the WNK1 pathway such as the OSR1 kinase remainsactive in these mice.This work provides the first in-depth characterization of NKCC1 regulation in neuronsand emphasize targeting the WNK1/SPAK/OSR1 pathway to regulate neuronal chloridehomeostasis and thus neuronal hyperactivity in epilepsy.
... Gramicidin perforated patch whole-cell recordings were performed similarly to previously described (Acton et al., 2012). Briefly, current-voltage (IV) curves were generated by step depolarizing the membrane potential in 10 mV increments from ∼−95 to −35 mV ( Figure 1C) and during each increment GABAergic transmission was elicited via extracellular stimulation in the stratum radiatum. ...
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mature brain but has the paradoxical property of depolarizing neurons during early development. Depolarization provided by GABAA transmission during this early phase regulates neural stem cell proliferation, neural migration, neurite outgrowth, synapse formation, and circuit refinement, making GABA a key factor in neural circuit development. Importantly, depending on the context, depolarizing GABAA transmission can either drive neural activity or inhibit it through shunting inhibition. The varying roles of depolarizing GABAA transmission during development, and its ability to both drive and inhibit neural activity, makes it a difficult developmental cue to study. This is particularly true in the later stages of development when the majority of synapses form and GABAA transmission switches from depolarizing to hyperpolarizing. Here, we addressed the importance of depolarizing but inhibitory (or shunting) GABAA transmission in glutamatergic synapse formation in hippocampal CA1 pyramidal neurons. We first showed that the developmental depolarizing-to-hyperpolarizing switch in GABAA transmission is recapitulated in organotypic hippocampal slice cultures. Based on the expression profile of K+−Cl− co-transporter 2 (KCC2) and changes in the GABA reversal potential, we pinpointed the timing of the switch from depolarizing to hyperpolarizing GABAA transmission in CA1 neurons. We found that blocking depolarizing but shunting GABAA transmission increased excitatory synapse number and strength, indicating that depolarizing GABAA transmission can restrain glutamatergic synapse formation. The increase in glutamatergic synapses was activity-dependent but independent of BDNF signaling. Importantly, the elevated number of synapses was stable for more than a week after GABAA inhibitors were washed out. Together these findings point to the ability of immature GABAergic transmission to restrain glutamatergic synapse formation and suggest an unexpected role for depolarizing GABAA transmission in shaping excitatory connectivity during neural circuit development.
... Nevertheless, both identified KCC2 variants, R1049C and R952H, significantly impaired the ability to extrude Cl − , resulting in cells with a higher basal [Cl − ] i and, thus, less hyperpolarization by GABA. These results are consistent with the suggested regulatory mechanisms of KCC2, i.e., its C-terminus, including the ISO domain (see Fig. 5), is required for isotonic KCC2 action (Acton et al., 2012;Medina et al., 2014). Interestingly, both KCC2 R952H and R1049C exhibited a significant decrease in S940 phosphorylation, despite comparable levels of total protein expression . ...
γ-Aminobutyric acid (GABA) generally induces hyperpolarization and inhibition in the adult brain, but causes depolarization (and can be excitatory) in the immature brain. Depolarizing GABA actions are necessary for neurogenesis, differentiation, migration, and synaptogenesis. Additionally, the conversion of GABA responses from inhibition to excitation can be induced in adults by pathological conditions. Because GABAA receptors are Cl- channels, alternating GABA actions between hyperpolarization (Cl- influx) and depolarization (Cl- efflux) are induced by changes in the Cl- gradient, which is regulated by Cl- transporters. Thus, the dynamics of neural functions are modulated by active Cl- homeostasis (Cl- homeodynamics), alternating inhibition and excitation, and could underlie the modal shifts in cellular and network oscillations. Such a modal shift in GABA actions is required for normal development. Thus disturbances in this developmental GABA modal shift and/or the induction of excitatory GABA action could underlie the pathogenesis of diverse neurological diseases (so-called network diseases).
... NKCC1 and KCC2 are comprised of 12 membrane-spanning segments, 6 extracellular loops, and intracellular N-and C-terminals. They differ in the position of regulatory sequences, phosphorylation sites, and long extracellular loops (25,31,32). In immature neurons, an age-specific upregulation of NKCC1 and a relative deficiency in KCC2 loads more Cl − into the cell, resulting in a net Cl − outflow and subsequent depolarization when GABA activates GABAa Rs. ...
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.
... No crystal structure is available for KCCs and NKCCs members so far. 35,37,40,41 . The main structural deviation between KCCs and NKCCs concerns the position of the long extracellular loop (LEL), which was shown to be localized between TM5 and TM6 in KCCs and between TM7 and TM8 in NKCCs 33 . ...
Cation chloride co-transporters (CCC) play an essential role for neuronal chloride homeostasis. CCC includes K⁺ Cl⁻ outward co-transporters (KCCs) and Na⁺ K⁺ Cl⁻ inward co-transporters (NKCCs). Although NKCCs and KCCs co-transporters have been studied intensively for several decades, a full picture of their common structural determinants and structure/function differences is still missing. A recent molecular architecture of KCC2 has been reported. This structure will be described and compared to high resolution structures of related co-transporters NKCC1 and KCC1 as well as previously reported biochemical and bioinformation information. Thus, the aim of this chapter is to provide a comprehensive overview of our current understanding of the architecture-function relationships of NKCCs and KCCs co-transporters. Differential cell expression profiles, sequence alignment, secondary structure prediction, structural comparison analysis, post-translational modification and oligomerization provide explanation of the subcellular and molecular organization and function of KCCs and NKCCs. This knowledge will enable structure-guided drug discovery allowing to meet many currently unmet medical needs related to neurological disorders and other human diseases.
... Under physiological conditions, KCC2 extrude chloride ions using the potassium gradient maintained by the Na/K ATPase. It is the only KCC working in isotonic conditions, thanks to its ISO domain (Acton et al., 2012). Since the reversal potential of both Cland K + ions are equal, KCC2 operates close to its thermodynamic equilibrium (Payne, 1997 (Avoli et al., 1996;Thompson et al., 1988). ...
Information transfer, storage and retrieval in the brain rely on a balance between excitation and inhibition. At the cellular level, memory encoding involves long-term potentiation of excitatory synapses, while at the network level, cortical rhythmogenesis underlies memory encoding and consolidation and requires inhibitory GABAergic signaling to synchronize neuronal ensembles. To maintain the efficacy and polarity of GABA transmission, the chloride/potassium co-transporter KCC2 controls the transmembrane chloride gradients. However, KCC2 also interacts with protein partners and influences neuronal membrane excitability as well as the function and plasticity of glutamatergic synapses. Altogether, KCC2 appears at the crossroads of excitatory and inhibitory transmission. During my PhD, I explored the consequences of KCC2 down-regulation in the dorsal hippocampus on learning and memory, and the underlying mechanisms both at the cellular and network levels. My results demonstrate that KCC2 knockdown in principal neurons of the dorsal hippocampus affects both spatial and contextual memory. This effect is associated with deficits in LTP of hippocampal synapses as well as neuronal hyperexcitability and hippocampal rhythmopathy, including abnormal sharp-wave ripple generation and gamma-band activity during sleep. These alterations likely contribute to impair both memory encoding and consolidation. Since KCC2 is down-regulated in many disorders associated with cognitive impairment, my results suggest that strategies aiming to restore KCC2 expression may hold therapeutic potential in these disorders. I therefore started testing this hypothesis in experimental models of Rett syndrome.
... This, in part, may be due to a decrease in stimulatory S940 phosphorylation [90]. Alternatively, interaction of these variants with the ISO domain (a unique 15 amino acid region on the KCC2 Cterminal domain) which has previously been identified as a vital component to KCC2 isotonic activity may cause the observed reduction in KCC2 function [91]. ...
Chloride (Cl ⁻ ) homeostasis is an essential process involved in neuronal signalling and cell survival. Inadequate regulation of intracellular Cl ⁻ interferes with synaptic signalling and is implicated in several neurological diseases. The main inhibitory neurotransmitter of the central nervous system is γ -aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl ⁻ permeable GABAA receptor channels (GABAAR) . This process is reliant on Cl ⁻ extruder K ⁺ -Cl ⁻ cotransporter 2 (KCC2), which generates the neuron’s inward, hyperpolarising Cl ⁻ gradient. KCC2 is encoded by the fifth member of the solute carrier 12 family ( SLC12A5) and has remained a poorly understood component in the development and severity of many neurological diseases for many years. Recent advancements in next-generation sequencing and specific gene targeting, however, have indicated that loss of KCC2 activity is involved in a number of diseases including epilepsy and schizophrenia. It has also been implicated in neuropathic pain following spinal cord injury. Any variant of SLC12A5 that negatively regulates the transporter’s expression may, therefore, be implicated in neurological disease. A recent whole exome study has discovered several causative mutations in patients with epilepsy. Here, we discuss the implications of KCC2 in neurological disease and consider the evolving evidence for KCC2’s potential as a therapeutic target.
