NEUROANATOMICAL INVESTIGATION OF HIPPOCAMPAL STRUCTURE IN TWO MOUSE MODELS OF WILLIAMS SYNDROME

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by a hemizygous deletion of approximately 26 genes on chromosome 7. Individuals with WS exhibit cognitive deficits consistent with functional alterations of the hippocampus, but the underlying structural impairments remain unknown. To determine how the WS hemideletion affects hippocampal structure, we aimed to provide quantitative data on its structural organization in two mouse models replicating the human WS hemideletion: the complete deletion (CD) model, retaining the Ncf1 gene, and the long deletion (LD) model, deleting Ncf1. This cross-model comparison assesses potential Ncf1-related vascular effects on brain structure. We used design-based stereological techniques on 50-μm thick Nissl-stained brain sections to estimate volume, neuronal number and soma size of the main hippocampal regions in wild-type and mutant mice. In both models, mutant mice showed a reduction in forebrain volume similar to that reported in individuals with WS, and reduced hippocampal volume. In LD mice, the decrease in hippocampal volume paralleled that of forebrain volume, whereas in CD mice it was proportionally greater. LD mice exhibited trends for smaller dentate gyrus, CA3, CA1, and subiculum, but no change in CA2. In contrast, all hippocampal regions were smaller in CD mice than in wild-type mice. The results of ongoing analyses on neuronal numbers in different hippocampal regions will be presented. Altogether, our findings show that the WS hemideletion impacts hippocampal structure and contributes to elucidating genotype-phenotype relationships in WS. Alterations in hippocampal structure likely contribute to spatial memory deficits, as observed in individuals with WS.