Impaired KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathogenesis.
KCC2 is a vital neuronal K+/Cl- co-transporter that is implicated in the etiology of numerous neurological diseases. It is subject to developmental dephosphorylation at threonine 906 and 1007, the functional importance of which remains unclear. We engineered mice with heterozygous phospho-mimetic mutations T906E and T1007E (KCC2E/+) to prevent the normal developmental dephosphorylation of these sites. Immature (P15) but not juvenile (P30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and higher seizure susceptibility. KCC2E/+ mice also had abnormal ultra-sonic vocalizations at P10-P12 and impaired social behavior at P60. Post-natal bumetanide treatment restored network activity at P15 but not social behavior at P60. Our data show that post-translational KCC2 regulation controls the GABAergic developmental sequence in vivo. The post-translational deregulation of KCC2 could be a risk factor for the emergence of neurological pathology and the presence of depolarizing GABA is not essential for manifestation of behavioral changes.