Table 1.

Effects of manipulation of CCC expression on neuronal chloride homeostasis

CCC	Model	Age	Effect	Refs
KCC2	Knockdown of gene encoding KCC2 in CA1 pyramidal neurons in rat organotypic HC slices	P11–13 (DIV 2–5)	Loss of hyperpolarizing DFGABA	2
	KCC2-null mouse spinal motor neurons	E18.5	Excitatory responses to GABA and glycine in knockout but not wild-type neurons	73
	KCC2b-null mouse spinal motor neurons	P5–8	EIPSP more positive than in wild-type neurons	178
	KCC2b-null mouse cultured cortical neurons	DIV 18–21	Lack of hyperpolarizing responses to GABA	4
	CA1 pyramidal neurons of compound-heterozygous KCC2 mice with lack of one allele and reduced expression of the second allele (mice retain ~20% of normal KCC2 brain expression)	P30	EGABA more positive than in wild-type neurons	177
	KCC2 overexpression in cultured rat HC neurons	DIV 5–7	Hyperpolarizing shift in EGABA to values observed in mature neurons; decrease in GABA-elicited Ca2+ responses	148,180
	KCC2 overexpression via in utero electroporation of rat or mouse layer 2/3 pyramidal neurons	P1–7	Hyperpolarizing shift in EGABA to values observed in mature neurons; enhancement of Cl− extrusion capacity	31,140, 181
	Knockdown of gene encoding KCC2 in cultured rat HC neurons	DIV 23–24	Loss of Cl− extrusion capacity	29,151
	Cell-specific KCC2-null, Cre–lox mouse cerebellar Purkinje neurons	P25–64	~60% decrease in hyperpolarizing DFGABA	5
	Cell-specific KCC2-null, Cre–lox mouse cerebellar granule cells	P30–62	Depolarizing shift in both Vm and EGABA	5
	KCC2 overexpression in embryonic zebrafish spinal cord neurons	26–32 HPF	Shift from depolarizing to hyperpolarizing DFGly	182
	Knockdown of gene encoding KCC2 in zebrafish retinal ganglion cells	2.5–6 DPF	Loss of somatodendritic and inter-dendritic EGABA gradients	179
KCC3	Cell-specific KCC3-null, Cre–lox mouse cerebellar Purkinje neurons	P25–64	No change in EGABA or DFGABA	5
	KCC3-null mouse cerebellar Purkinje neurons	P12–14	EGABA more positive than in wild-type neurons	116
	KCC3-null mouse DRG sensory neurons	Adult	Increase in [Cl−]i compared to wild-type neurons	51
NKCC1	Knockdown of gene encoding NKCC1 in newborn DGCs of adult mouse	P49–56	Loss of depolarizing DFGABA	296
	NKCC1-null mouse CA1 pyramidal neurons	P1	Decrease in depolarizing DFGABA ; decrease in GABA-elicited Ca2+ responses	94
	NKCC1-null mouse CA1 pyramidal neurons	P3–4	Loss of depolarizing DFGABA	10
	NKCC1-null mouse CA3 pyramidal neurons	P6–7	Loss of depolarizing DFGABA	97
	NKCC1-null mouse DGCs	P16–20	Loss of axosomatic EGABA gradient	185

CCC, cation-chloride cotransporter; [Cl⁻]_i, intracellular Cl⁻ concentration; DF_GABA, the driving force of the GABA_A receptor (GABA_AR)-mediated current; DGC, dentate granule cell; DIV, day in vitro; DPF, days post-fertilization; DRG, dorsal root ganglion; E, embryonic day; E_GABA, the reversal potential of GABA_AR-mediated responses; E_IPSP, reversal potential of inhibitory postsynaptic potentials (IPSPs); HC, hippocampal; HPF, hours post-fertilization; KCC, K⁺–Cl⁻ cotransporter; NKCC, Na⁺–K⁺–2Cl⁻ cotransporter; P, postnatal day; V_m, membrane potential.