Mechanisms of epileptogenesis in KCNA2-/SCN2A-mediated epilepsies

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The development of new effective treatment strategies for severe drug-resistant epilepsies such as epileptic encephalopathies (EE) is largely hampered by the lack of knowledge about the mechanisms of seizure generation. Besides the severity and pharmacoresistance, EEs are accompanied by intellectual disability and other neurodevelopmental impairments. The cause of progressive cognitive deterioration is unknown; frequent seizures during development or gene defects themselves are the most likely candidates. Here, we will use mouse models of genetic epilepsies to study epileptogenesis during brain development and investigate the pathophysiology of both loss- and gain-of-function (LOF/GOF) mutations in the KCNA2 gene, encoding the voltage-gated K+ channel KV1.2 that we recently identified as a cause of EE1(H) and, in collaboration with P5, P7 and P8, a GOF mutation in the SCN2A gene, encoding the voltage-gated Na+ channel NaV1.22. We will use Kcna2 and Scn2a KI mouse models as well as in utero electroporation/viral transduction (IUE/IUVT) techniques to (i) identify morphological and transcriptional changes caused by GOF or LOF mutations in KV1.2 channels; (ii) characterize the in vitro and in vivo activity patterns of genetically modified cortical neurons (inhibitory vs excitatory) during age-dependent development of epileptiform activity; (iii) identify aberrant activity patterns triggering seizure generation, and the cortical regions as well as cell types involved; (iv) analyze spatial and temporal aspects of propagation of the epileptiform activity within the in vivo cortex and (v) test the hypothesis that this activity is caused by pathological amplification of endogenous cortical rhythms. In addition, we will test if early pharmacological treatments antagonize the neuropathological consequences of the above mentioned mutations.