Highlights d KCC2 interacts with Task-3 potassium channels and regulates their membrane traffic d KCC2 knockdown depolarizes rat hippocampal neurons and increases their excitability d Chronic KCC2 knockdown in rat dentate gyrus is not sufficient to induce seizures d Network activity is altered by KCC2 knockdown, mostly independent of GABA signaling

Cation-chloride cotransporters (CCCs) play a critical role in controlling the efficacy and polarity of GABA A receptor (GABA A R)-mediated transmission in the brain, yet their expression and function in GABAergic interneurons has been overlooked. r We compared the polarity of GABA signalling and the function of CCCs in mouse hippocampal pyramidal neurons and parvalbumin-expressing interneurons. r Under resting conditions, GABA A R activation was mostly depolarizing and yet inhibitory in both cell types. KCC2 blockade further depolarized the reversal potential of GABA A R-mediated currents often above action potential threshold. r However, during repetitive GABA A R activation, the postsynaptic response declined independently of the ion flux direction or KCC2 function, suggesting intracellular chloride build-up is not responsible for this form of plasticity. r Our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal pyramidal neurons and parvalbumin interneurons.