AUTHOR=Khalilov Ilgam , Chazal Geneviève , Chudotvorova Ilona , Pellegrino Christophe , Corby Severine , Ferrand Nadine , Gubkina Olena , Nardou Romain , Tyzio Roman , Yamamoto Sumii , Jentsch Thomas J., Hubner Christian , Gaiarsa Jean-Luc , Ben-Ari Yehezkel , Medina Igor TITLE=Enhanced Synaptic Activity and Epileptiform Events in the Embryonic KCC2 Deficient Hippocampus JOURNAL=Frontiers in Cellular Neuroscience VOLUME=5 YEAR=2011 URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2011.00023 DOI=10.3389/fncel.2011.00023 ISSN=1662-5102 ABSTRACT=

The neuronal potassium-chloride co-transporter 2 [indicated thereafter as KCC2 (for protein) and Kcc2 (for gene)] 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 GABA-ergic postsynaptic currents 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 immunolabeling 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 GABA-ergic 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 synapse formation and networks construction.