Enhanced synaptic activity and epileptiform events in the embryonic Kcc2 deficient hippocampus

• Main Authors: Ilgam eKhalilov, Geneviève eChazal, Ilona eChudotvorova, Christophe ePellegrino, Severine eCorby, Nadine eFerrand, Olena eGubkina, Romain eNardou, Roman eTyzio, Sumii eYamamoto, Thomas J Jentsch, Christian eHubner, Jean-Luc eGaiarsa, Yehezkel eBen-Ari, Igor eMedina
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2011-11-01
• Series: Frontiers in Cellular Neuroscience
• Subjects: development; GABA; KCC2; network; Neuron; synapse
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fncel.2011.00023/full

The neuronal potassium-chloride co-transporter Kcc2 is thought to play an important role in the post natal excitatory to inhibitory switch of GABA actions in the rodent hippocampus. Here, by studying hippocampi of wild-type (Kcc2+/+) and Kcc2 deficient (Kcc2-/-) mouse embryos, we unexpectedly found increased spontaneous neuronal network activity at E18.5, a developmental stage when Kcc2 is thought not to be functional in the hippocampus. Embryonic Kcc2-/- hippocampi have also an augmented synapse density and a higher frequency of spontaneous glutamatergic and GABAergic postsynaptic currents (PSCs) than naïve age matched neurons. However, intracellular chloride concentration ([Cl-]i) and the reversal potential of GABA-mediated currents (EGABA) were similar in embryonic Kcc2+/+ and Kcc2-/- CA3 neurons. In addition, Kcc2 immuno-labelling was cytoplasmic in the majority of neurons suggesting that the molecule is not functional as a plasma membrane chloride co-transporter. Collectively, our results show that already at an embryonic stage, Kcc2 controls the formation of synapses and, when deleted, the hippocampus has a higher density of GABAergic and glutamatergic synapses and generates spontaneous and evoked epileptiform activities. These results may be explained either by a small population of orchestrating neurons in which Kcc2 operates early as a chloride exporter or by transporter independent actions of Kcc2 that are instrumental in synapses formation and networks construction.