Functional analysis of the epilepsy gene Pcdh19 using a novel GFP-reporter mouse model

Abstract

AbstractMutations in the X-linked genePCDH19are the cause of PCDH19-Clustering epilepsy, an infantile-onset disorder characterized by seizures and intellectual disabilities. Although several intra and extracellular functions of PCDH19 have been identified, the spatiotemporal impact ofPcdh19deletionin vivois poorly understood. To investigate the consequences of eliminatingPcdh19in specific cell and brain regions, we generated a novelPcdh19floxed mouse with a GFP reporter (Pcdh19-cKO-GFP). UsingPcdh19-cKO-GFP andSyn1-Cre mouse lines we demonstrated thatPcdh19elimination in neurons leads to abnormal hippocampal neurogenesis and impaired mouse behaviour. To assess the impact of region-specific elimination ofPcdh19on brain physiology we used aGfap-Cre mice line. SpecificPcdh19deletion in the hippocampus resulted in increased neurogenesis and decreased memory formation. Finally, we assessed the feasibility of using our conditional mouse model for stage-specificPcdh19elimination during embryogenesis using a Dox-inducible Cre-deletor line. Taken together, these results demonstrate the utility of our uniquePcdh19-cKO-GFP mouse model to investigate PCDH19 function in brain physiology and pathology.