Highlights The chloride (Cl-) levels in GABAergic neurons are controlled by two SLC12 cation-chloride-cotransporters (CCCs): Na + /K + /Cl − co-transporter NKCC1 and K + /Cl − co-transporter KCC2, that respectively cause an influx and efflux of Cl-., and thereby controls GABA signalling in the brain. Altered expression and/or activity of either NKCC1 or KCC2 co-transporters in suprachiasmatic nucleus (SCN) have been associated with circadian rhythms. CCCs and their upstream regulators present many promising points of interventions for circadian disruption. 4. A novel strategy has been proposed to facilitate neuronal Cl- extrusion by coincident NKCC1 inhibition and KCC2 activation by inhibiting the WNK3-SPAK/OSR1 signaling pathway with the newly developed SPAK inhibitor, ZT-1a.