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.
Highlights
Kcc2 is a potassium-chloride co-transporter that is exclusively expressed in neurons of central nervous system (CNS; Payne et al, 1996; Williams et al, 1999)
We report that already at E18.5, Kcc2−/− mice hippocampal networks generate spontaneous epileptiform events and neurons have more GABA-ergic and glutamatergic synapses and currents than wild-type embryos (Kcc2+/+) suggesting a requirement for the co-transporter in embryos
The most conspicuous result of our study is that the ongoing neuronal activity is dramatically increased in hippocampi isolated from Kcc2−/− embryos when compared to age matched naïve structures
Summary
Kcc is a potassium-chloride co-transporter that is exclusively expressed in neurons of central nervous system (CNS; Payne et al, 1996; Williams et al, 1999). It plays an important role in regulating intracellular chloride concentrations ([Cl−]i), thereby heavily impacting the magnitude of the inhibitory action of GABA in physiological processes (Rivera et al, 1999). The expression of KCC2 is thought to lead to a reduction of [Cl−]i and a shift of the actions of GABA from excitation to inhibition, other chloride regulators – channels and transporters – take part in this sequence (Medina and Chudotvorova, 2006; Blaesse et al, 2009)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
