The purpose of this component project is to carry out a neuroanatomical analysis of the brain in Williams Syndrome (WMS) to shed light on the interface between genetic abnormality and behavioral disorder. The brain in WMS exhibits the following: curtailment of the posterior portion of the forebrain; foreshortening of central sulci dorsally; decrease in volume of the amygdalar nuclei; decreased asymmetry; normal cytoarchitecture; acquired microvascular pathology; laminar-specific decrease neuronal size and increase cell packing density; absence of staining for Elastin in cerebellum; and normal staining for Lim-12 kinase. Curtailment of development of the posterior and dorsal portions of the hemispheres is compatible with the visuo-spatial problem seen in WMS; it may also be compatible with the relative sparing of function linked to more ventral cortices, such as face recognition and language and musical abilities. Acquired microvascular pathology in the same dorsal regions implicates the same behaviors and may represent additive pathology. Involvement of the amygdala, particularly the lateral nuclei, implicates the limbic system and may contribute to the personality typical of WMS. Decrease in cell size with increase in cell packing density, together with a smaller brain, suggests an overall paucity of projection neurons with accompanying changes in connectivity. The absence of Elastin staining but normal Lim- 1 kinase staining indicates a differential effect off hemideletion on gene expression. Additional brains will be collected. Appropriate sections will undergo semi-automated image processing for cell size and cell numbers. We will also look at differences between dorsal and ventral cortical areas, frontal and posterior, cortical and subcortical vis a vis acquired neuropathology, architectonic pathology, histometric differences and gene expression in order to test the hypothesis that particularly dorsal portions of the hemispheres are affected. We will also investigate the amygdala further to test the hypothesis that this nucleus is abnormal and that the limbic portions of this nucleus are particularly affected in WMS. Finally, we will begin to look at putative animal models by assaying GTF2I/IRD knock- outs anatomically and behaviorally. The results of these studies will help guide additional research aiming at looking at the steps between genomic lesion, messenger, and product expression leading to abnormal development in the WMS brain, and may shed additional light on normal brain and behavioral development.
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