Cell-type specific determinants of epileptic syndromes associated with KCC2 mutations – EpiK

Altered neuronal chloride homeostasis is emerging as a hallmark of neurological and psychiatric disorders, including epilepsy, autism spectrum disorders, and schizophrenia. Defects in the expression or function of the cation and chloride cotransporters KCC2 and NKCC1 are associated with these disorders and are thought to impair inhibitory signaling through GABAA receptors. Several recent studies have reported missense or deletion-inducing mutations in the SLC12A5 gene (encoding KCC2) as risk factors for neurological disorders associated with epilepsy, including childhood epilepsy with focal migrating seizures (EIMFS), a severe epileptic encephalopathy characterized by focal migrating seizures and intellectual disability. However, the pathophysiological mechanisms by which these mutations promote the development of epilepsy remain unexplored. Based on the recent discovery of non-canonical KCC2 functions affecting developmental apoptosis and neuronal maturation, we hypothesize that pathogenic SLC12A5 mutations may have a much broader functional impact than previously thought, involving neurodevelopmental alterations.
The main goal of the EpiK project is to elucidate the molecular and cellular determinants of epileptic neurodevelopmental disorders associated with SLC12A5 mutations. This will be achieved by combining molecular and cellular characterization with cell type-specific functional studies of cortical development, synaptic function and rhythmogenesis in two novel mouse models. EpiK brings together 4 internationally renowned research groups with complementary scientific expertise and a converging interest in the molecular mechanisms underlying neurodevelopmental disorders associated with epilepsy. By combining state-of-the-art multimodal approaches to study the impact of SLC12A5 mutations on cortical development and function, EpiK will reveal cell-type specific mechanisms for neurodevelopmental epilepsy and identify novel entry points for therapeutic intervention.