Chloride Homeostasis And Gabaergic Inhibition

Fast synaptic inhibition in the central nervous system is primarily facilitated by the activation of GABAA receptors, members of the cysteine-loop ligand-gated ion channel superfamily. GABAA receptors consist of five subunits which form a central anion-selective pore that opens in the presence of the neurotransmitter GABA [2]. The diversity of the subunit combinations, juxtaposed with their varying global and temporal expression patterns and subcellular targeting, leads to a complex group of GABA receptor subtypes with different functional and pharmacological properties.

Moreover, GABAA receptors are almost four times more permeable to Cl− than to HCO3−[3]. Therefore, in most neurons, the reversal potential of signaling through GABAA receptors (EGABA) lies closer to the Cl− reversal potential (ECl) than to the more positive (EHCO3 )2, 4. This relationship between EGABA and ECl positions [Cl−]i acts as a marking feature of the strength of fast-synaptic inhibition.

In early stages of brain development, neurons have high [Cl−]i ensuing in depolarizing responses to GABAA receptor activation [5]. Over the course of brain development, as neurons mature, Cl− can be extruded, which results in hyperpolarizing GABAA receptor currents [6]. This difference in [Cl−]i between the mature and immature nervous system occurs principally due to changes in the expression levels and activity of two cation–chloride cotransporters, Na+–K+–Cl− cotransporter 1 (NKCC1) and type 2 K+–Cl− cotransporter (KCC2). NKCC1, a symporter, is highly expressed in neural precursor cells and during early brain development (7, 8). The action Na+–K+-ATPase (Na/K pump) creates a intracellularly directed sodium gradient that is used by NKCC1 to drive Cl− into the cell. Contrarily, KCC2 combines the extracellularly directed K+ gradient to extrude Cl− from the cell against its electrochemical gradient but is absent in immature neurons 9, 10. In the mature brain, NKCC1 function is downregulated while KCC2 function increases 8, 10. This causes a marked reduction in [Cl−]i as development proceeds, causing a depolarizing to hyperpolarizing shift in EGABA[6]. Therefore, the inhibitory actions of GABA directly depend on the Cl− driving force upheld by the intracellular concentration of Cl− ([Cl−]i). KCC2, a neuron-specific cotransporter, is encoded by SLC12A5 in humans. KCC2 is the main Cl− extruder of neurons, so it is of critical importance for the maintenance of low [Cl−]i levels in neurons. Consequently, the appropriate inhibitory function of GABA is preserved by the correct functioning of KCC2. (Ben-Ari, 2002; Kaila, Price, Payne, Puskarjov, & Voipio, 2014; Owens & Kriegstein, 2002)⁠

SLC12A5 two neuron-specific isoforms, KCC2a and KCC2b (Uvarov et al., 2007). KCC2b shows a dramatic increase in expression during postnatal development. In contrast, KCC2a, which is essential for modulation of neonatal respiratory neural networks (Dubois et al., 2018), remains relatively constant, and then decreases to contribute only a part of the total KCC2 in the mature brain. In this review, KCC2 denotes KCC2b, unless otherwise mentioned.