| Popis: |
Mutations in the X-linked cell adhesion protein PCDH19 lead to seizures, cognitive impairment and other behavioral comorbidities when present in a mosaic pattern. Neither the molecular mechanisms underpinning this disorder, nor the function of PCDH19 itself are well understood. By combining RNA in situ hybridization with immunohistochemistry and analyzing single cell RNAseq datasets, we reveal Pcdh19 expression in cortical interneurons and provide a first account of the subtypes of neurons expressing Pcdh19/PCDH19, both in the mouse and the human cortex. Our quantitative analysis of the Pcdh19 mutant mouse exposes subtle changes in cortical layer composition, with no major alterations of the main axonal tracts. In addition, Pcdh19 mutant animals, particularly females, display preweaning behavioral changes, including reduced anxiety and increased exploratory behavior. Importantly, our experiments also reveal an effect of the social environment on the behavior of wild-type littermates of Pcdh19 mutant mice, which show alterations when compared with wild-type animals not housed with mutants. SIGNIFICANCE STATEMENT PCDH19 mutations cause epileptic encephalopathy in humans, but the underlying pathophysiology is not completely understood. Here, we provide the first quantitative analysis of the cortical neuronal types expressing Pcdh19 in the mouse and human neocortex, and of cortical layer composition in Pcdh19 mutant animals, revealing expression of Pcdh19 in interneurons and the presence of small, but significant changes in neuronal distribution. The findings of our behavioral analysis indicate not only reduced anxiety and increased exploratory behavior, but also an impact of the mutant genotype on the behavior of wild-type animals when housed in the same cage. This finding underscores the importance of selecting appropriate control cohorts to avoid missing relevant behavioral changes in mutant animals. |
