gms | German Medical Science

Objective: Over the course of the last years several idiopathic epilepsy syndromes and more recently also epileptic encephalopathies have been linked to ion channel mutations. Numerous mutations (e.g. KV7 potassium channel mutations) have been analyzed in heterologous expression systems (for example Xenopus oocytes) and in few instances in gene-targeted mouse models. Although such studies lead to a better understanding of the underlying disease mechanisms many questions remain elusive. KV7 mutations are known to cause BFNS (benign familial neonatal seizures), an epilepsy syndrome, which was thought to follow a rather benign course. However, over the past years an increasing amount of clinical and genetic data suggested that the phenotypic spectrum might be broader than initially thought. Recently, this was confirmed by a study linking severe cases of epileptic encephalopathy to KV7 mutations. The underlying mechanisms are currently not understood and cannot be sufficiently addressed in vitro.

Method: We propose to employ state-of-the-art techniques including in-utero electroporation, stereotaxic retrograde labeling of cortical projection neurons, optogenetics and neuronal transplantation to investigate the pathophysiological mechanism of ion-channel mutations in vivo and to reapply the gained knowledge to explore novel therapeutic options.

Results: TVW has used these approaches extensively during a 4-year postdoctoral training abroad within the field of developmentally driven CNS repair and aims to bring these techniques into the field of neurosurgically motivated epilepsy research.

Conclusions: Merging the fields of developmental and regenerative biology and experimental epileptology will enable innovative experiments to study neurobiological aspects of the pathophysiology of epilepsy and epileptic encephalopathy such as neuronal migration defects, impaired neuronal axon extension (e.g. transcallosal) and altered neuronal morphology and connectivity. These results will provide the foundation for the development of novel interdisciplinary therapeutic concepts in the treatment of epilepsy.