KCC2-Mediated Cl− Extrusion Modulates Spontaneous Hippocampal Network Events in Perinatal Rats and Mice

Abstract

Summary: It is generally thought that hippocampal neurons of perinatal rats and mice lack transport-functional K-Cl cotransporter KCC2, and that Cl− regulation is dominated by Cl− uptake via the Na-K-2Cl cotransporter NKCC1. Here, we demonstrate a robust enhancement of spontaneous hippocampal network events (giant depolarizing potentials [GDPs]) by the KCC2 inhibitor VU0463271 in neonatal rats and late-gestation, wild-type mouse embryos, but not in their KCC2-null littermates. VU0463271 increased the depolarizing GABAergic synaptic drive onto neonatal CA3 pyramidal neurons, increasing their spiking probability and synchrony during the rising phase of a GDP. Our data indicate that Cl− extrusion by KCC2 is involved in modulation of GDPs already at their developmental onset during the perinatal period in mice and rats. : Immature hippocampal pyramidal neurons are thought to lack chloride extrusion mediated by K-Cl cotransporter KCC2. Spoljaric et al. demonstrate that KCC2 restrains the depolarizing GABAergic synaptic drive onto CA3 pyramidal neurons in perinatal mice and rats and thereby regulates spontaneous hippocampal network events (GDPs) from their developmental onset. Keywords: chloride, cation-chloride cotransporter, pacemaker, bumetanide, critical window, correlated activity, KCC2 knockout