Modeling neurodevelopmental epilepsy syndromes: the example of mosaic deletion of PCDH19 and its influence on tangential migration of interneurons.

This project aims at elucidating a mechanism behind a genetic disorder, using the developing mouse brain as a study object.  Brain function depends on the maintenance of a balance between excitatory and inhibitory signals, emanating from different neuron and interneuron populations, respectively. When this balance is disrupted, conditions like epilepsy, intellectual dysfunction and autism can occur. Cortical interneurons develop in the basal forebrain during embryogenesis and travel over long distances towards the cortex. Our recent work indicated that defects in interneuron migration in the mouse lead to epilepsy. In human, mutations in the X-linked gene PCDH19 lead to EIEE8, a developmental encephalopathy characterized by severe epilepsy and intellectual disability in females, whereas males are found to have autism, but no seizures. This is uncommon, because in most X-linked disorders, males are more affected. Our hypothesis is that the mosaic absence of PCDH19 in affected females impacts the adhesion of developing interneurons, leading to migration problems. This project aims to establish ex vivo and in vivo mouse models of EIEE8 in which PCDH19 is deleted in a limited number of interneuron precursors by electroporation of brain slices or specific brain regions in utero. If successful, this approach can be adapted to model any forebrain-related developmental encephalopathy