NKCC1 and KCC2 Simple review

In Development,
GABA release from GABAergic interneuron,
--> [Cl-]i efflux (release)

     in GABAA receptors (GABA receptor mediated Cl ion channel (gradient))  

     in pyramidal neurons (target or postsynaptic neuron of GABAergic interneuron) 

  --> Depolarization (because intracellular negative ion is decreased)

    --> Excitation in pyramidal neuron

GABA release --> GABA binding GABAA receptor --> [Cl-]i efflux --> depol --> excitation in target neuron

FROM THE FOLLOWING ARTICLE:
Excitatory actions of gaba during development: the nature of the nurture
Yehezkel Ben-Ari
Nature Reviews Neuroscience 3, 728-739 (September 2002)


FIGURE 1 | Early expression of NKCC1 and late expression of KCC2 determines developmental changes in [Cl-]i.

Schematic diagram depicting the Na+–K+–2Cl- co-transporter NKCC1, the K+–Cl- co-transporter KCC2 and voltage-gated calcium currents, as well as the gradients of chloride ions. 

a | NKCC1 expression predominates in immature neurons, in which the intracellular concentration of chloride ([Cl-]i) is relatively high.

b | KCC2 expression predominates in mature neurons.

Note that the activation of GABA (-aminobutyric acid) type A receptors generates an efflux of chloride and an excitation of immature neurons, and an influx of chloride and an inhibition of adult neurons. 

CLC2, voltage-gated chloride channel 2; ECl, chloride reversal potential; RMP, resting membrane potential (Vrest); VDCC, voltage-dependent calcium channel. Adapted, with permission, from Ref. 42 © 1998 The American Physiological Society.


Nature Medicine 11, 1153 - 1154 (2005)
doi:10.1038/nm1105-1153
Diuretic soothes seizures in newborns


Figure 1. Model of bumetanide action on neonatal seizures.
GABAergic interneurons activate synaptic GABAA receptors on pyramidal neurons. The pyramidal cells are interconnected, and release glutamate when excited, thus activating postsynaptic glutamate receptors (GLU-R). 

(a) Immature pyramidal neurons have high concentrations of Cl-. The neurons take up Cl- by NKCC1, an inwardly-directed Na+,K+-2Cl- cotransporter, overwhelming Cl- extrusion by KCC2, an outwardly-directed K+-Cl-cotransporter. 

The Cl- equilibrium potential is therefore positive to the resting membrane potential, and activation of GABAA receptor-channels results in Cl- efflux and depolarization. 

This depolarization (and excitation) may cause the release of glutamate, which further induces excitation by activation of GLU-R, rendering neonatal cortex highly susceptible to seizures.Thus, NKCC1 activity facilitates neonatal seizures. 

(b) Low-dose bumetanide selectively inhibits NKCC1 activity. Dzhala et al. find that this inhibition causes intracellular Cl- to fall and reduces or reverses the depolarizing action of GABA —as a result, the cell experiences an influx of Cl- and hyperpolarizes. This prevents excitation of the pyramidal neuron and subsequent release of glutamate from their terminals. Through this mechanism, bumetanide could suppress epileptiform discharges in the developing brain.