Diurnal rhythm in cortical chloride homeostasis underpins functional changes in visual cortex excitability

Abstract Fast synaptic inhibition is a primary determinant of cortical activity patterns, and it is mediated predominantly by ionotropic, chloride-conducting receptors. Consequently, modulation of chloride homeostasis is ideally placed to regulate activity. We therefore investigated the stability of steady-state [Cl-]i in adult mice neocortex, using in vivo two photon imaging. We found a two-fold increase in baseline [Cl-]i in layer 2/3 pyramidal neurons, from day to night, with marked effects upon both physiological cortical processing and seizure susceptibility. Importantly, the night-time activity can be converted to day-time patterns by local inhibition of NKCC1. Consistent with these findings, the surface expression and phosphorylation states of the cation-chloride cotransporters, NKCC1 and KCC2, are diurnally modulated, with reduced chloride extrusion capacity at night. These data indicate that [Cl-]i modulation is likely to be an important determinant of variable cortical excitability, through the day.