Disruption of KCC2 in parvalbumin-positive interneurons causes fatal epilepsy in mice

Since many years, we are interested in the regulation of the intraneuronal chloride concentration. We were the first group reporting a full knockout of the KCl-co-transporter KCC2, which dies immediately after birth due to respiratory failure. Notably, KCC2 loss-of-function mutations are associated with inherited febrile seizures, severe genetic generalized epilepsy and epilepsy of infancy with migrating focal seizures. Here, we used our floxed line to study the consequences of the disruption of KCC2 within parvalbumin-positive interneurons in mice. Remarkably, this leads to the disinhibition of PV-positive interneurons as evidenced by a decrease of E-S-Coupling and an increase in the sIPSC frequency. Nevertheless, these mice develop fatal epilepsy with progressive loss of parvalbumin-positive interneurons thus increasing network excitability.