Anion transport and GABA signaling

Abstract

Whereas activation of GABAA receptors by GABA usually results in a hyperpolarizing influx of chloride into the neuron, the reversed chloride driving force in the immature nervous system results in a depolarizing efflux of chloride. This GABAergic depolarization is deemed to be important for the maturation of the neuronal network. The concept of a developmental GABA switch has mainly been derived from in vitro experiments and reliable in vivo evidence is still missing. As GABAA receptors are permeable for both chloride and bicarbonate, the net effect of GABA also critically depends on the distribution of bicarbonate. Whereas chloride can either mediate depolarizing or hyperpolarizing currents, bicarbonate invariably mediates a depolarizing current under physiological conditions. Intracellular bicarbonate is quickly replenished by cytosolic carbonic anhydrases. Intracellular bicarbonate levels also depend on different bicarbonate transporters expressed by neurons. The expression of these proteins is not only developmentally regulated but also differs between cell types and even subcellular regions. In this review we will summarize current knowledge about the role of some of these transporters for brain development and brain function.

KCC2 function modulates in vitro ictogenesis

“…Blocking KCC2 activity should increase intra-cellular [Cl − ] but Viitanen et al (2010) have reported that this change does not influence GABA A receptor-mediated hyperpolarizations and slightly shifts their reversal potential which remains more negative than the resting membrane potential. The lack of meaningful effects on GABA A receptor-mediated hyperpolarizations could be due to the contribution of the Na + dependent anion exchanger (NDAE), which extrudes Cl − and H + and loads and Na + (Payne et al, 2003;Hübner and Holthoff, 2013). Activation of NDAE can promote the inhibitory action of GABA by maintaining Cl − reversal potential negative to the resting membrane potential (Hübner and Holthoff, 2013).…”

“…The lack of meaningful effects on GABA A receptor-mediated hyperpolarizations could be due to the contribution of the Na + dependent anion exchanger (NDAE), which extrudes Cl − and H + and loads and Na + (Payne et al, 2003;Hübner and Holthoff, 2013). Activation of NDAE can promote the inhibitory action of GABA by maintaining Cl − reversal potential negative to the resting membrane potential (Hübner and Holthoff, 2013). Although GABA A receptor-mediated signaling remains hyperpolarizing, KCC2 blockers may influence the duration of the pharmacologically isolated GABAergic events by slightly shifting the E GABA and altering the ability of postsynaptic neurons to accumulate Cl − .…”

GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo

“…The developmental depolarizing-to-hyperpolarizing GABA shift is thought to reflect a developmental decline in intracellular chloride concentration ([Cl -] i ) due to a differential expression/ efficacy of plasmalemmal chloride-accumulating (for example NKCC1 5-7 ) versus chloride-extruding (for example KCC2 (ref. 8) co-transporters 9,10 . By facilitating the generation of action potentials, GABA was further found to promote the generation of patterned network activity 3,[11][12][13][14][15] .…”

Functions of GABAergic transmission in the immature brain

“…Intense GABA A R activation may therefore cause a rapid collapse of the driving force of chloride, but not bicarbonate. This mechanism may mediate GABA A R-dependent depolarization in adult neurons which will result in a further passive chloride load (see Hübner & Holthoff, 2013).…”