The Multifaceted Roles of KCC2 in Cortical Development

Abstract

KCC2, best known as the neuron-specific chloride-extruder that sets the strength and polarity of GABAergic currents during neuronal maturation, is a multifunctional molecule that can regulate cytoskeletal dynamics via its C-terminal domain (CTD). We describe the molecular and cellular mechanisms involved in the multiple functions of KCC2 and its splice variants, ranging from developmental apoptosis and the control of early network events to the formation and plasticity of cortical dendritic spines. The versatility of KCC2 actions at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease, and aging. Thus, KCC2 has emerged as one of the most important molecules that shape the overall neuronal phenotype. KCC2 in the Fundamental Machinery Underlying Neuronal Development, Signaling, and StructureFast synaptic transmission relies on ion fluxes through ligand-gated ion channels. Although the default state of a cell is to have a high intracellular chloride concentration ([Cl − ] i ), mature neurons in the CNS have evolved a unique ability to maintain a low [Cl − ] i , which is needed for the generation of hyperpolarizing Cl − currents across GABA A and glycine receptors (GABA A Rs and GlyRs) [1]. This specialization comes at a high energy cost [2], and is brought about by upregulation of the neuron-specific K-Cl cotransporter KCC2 during neuronal maturation [1,3,4]. KCC2 belongs to the evolutionarily ancient family of SLC12 cation/chloride cotransporters (CCCs) (Box 1; for KCCs and NKCCs, see Glossary) that have their roots in a single gene in Archaea, from which numerous duplication events in both archaeans and eukaryotes have led to the divergence and neofunctionalization of the paralogous CCC subfamilies [5]. Possibly because of a primordial role in cellular volume regulation, CCCs have evolved to communicate with the actin cytoskeleton. Indeed, KCC2 has emerged as an important player in controlling actin dynamics during neuronal development and plasticity [6][7][8][9].The functional upregulation of KCC2-mediated K-Cl cotransport in hippocampal and neocortical neurons underlies the hyperpolarizing shift in GABAergic currents which takes place postnatally in rats and mice [3], but it has become clear that KCC2 is expressed at low but functionally significant levels pre-and perinatally. KCC2 acts in an ion transport-independent manner as an antiapoptotic factor in projection neurons in the prenatal mouse neocortex [10]; in the perinatal mouse and rat hippocampus transport-functional KCC2 decreases the depolarizing driving force of GABA A R-mediated currents (DF GABA ), thereby influencing spontaneous network events at their developmental onset [11].In this review we highlight the developmental paths from KCC2 protein expression to its multiple functions, and discuss the wide variety of post-translational mechanisms which control these phenomena. The versatility of KCC2 regulation at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease,...

The Chloride Homeostasis of CA3 Hippocampal Neurons Is Not Altered in Fully Symptomatic Mepc2-null Mice

“…Tang et al (2016) have shown that KCC2 is a target of Mecp2 and that compounds enhancing the expression of KCC2 rescued the morpho-functional abnormalities of human RTT neurons and exerted therapeutic effects in early symptomatic Mecp2 −/y mice (Tang et al, 2019). Based on our study, this therapeutic action may be accounted for by a rescue of chloride homeostasis in non-hippocampal brain regions or, alternatively, mediated through interactions with a wide range of cytoskeleton-associated and/or membrane proteins, independent of its Cl − transport function (Virtanen et al, 2021), as reported for the regulatory role of KCC2 on spines formation (Li et al, 2007), synaptic plasticity (Gauvain et al, 2011;Chevy et al, 2015), and neuronal excitability (Goutierre et al, 2019). Examination of chloride homeostasis in additional brain regions at symptomatic stages would be interesting to address these points.…”

Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington’s Disease

“…Without KCC2, dendritic spine morphology is compromised, producing stubby structures that compromise the function of excitatory synapses (Li et al, 2007). Indeed, with the broad functions (independent of ion transport) of KCC2, it's no surprise that reduced GABAergic inhibition is not the only phenotype in KCC2-related pathologies and may contribute to other symptoms in HD (Tang, 2020;Virtanen et al, 2021).…”

Neurophysiology of the Developing Cerebral Cortex: What We Have Learned and What We Need to Know

“…In vivo reports (Kirmse et al, 2015 ; Murata and Colonnese, 2020 ) and modeling studies (Lombardi et al, 2021 ) provide a more complex picture of the developmental shift in GABA action, especially when on-going spatiotemporal interactions between GABAergic and glutamatergic inputs are taken into account (for review Kilb, 2021 ). It is not the aim of this short review to summarize the current data on this topic, but it is well-accepted that the intracellular chloride concentration is regulated by development, various molecular factors, and neuronal activity (Kaila et al, 2014 ; Watanabe and Fukuda, 2015 ; Virtanen et al, 2020 , 2021 ). Thus, the action and function of the important neurotransmitter GABA, and also glycine and taurine (for review Kilb and Fukuda, 2017 ), changes dramatically during the first postnatal week in rodent cortex!…”