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. it is not common to have the opportunity to study the brain in a condition where the genetic abnormality is available to understanding and the behavioral abnormality is well characterized. Our colleagues have described gross anatomical anomalies in neuroimaging studies of WMS and more recently we have shown in one autopsy specimen the presence of gross anatomical, architectonic and histological abnormalities. Prior to generating hypotheses about how the particular genetic abnormality of WMS leads to brain anomalies and in turn to behavioral deficits, it is important to determine how consistent these early findings ar. Preliminary hypotheses would suggest that the early hypercalcemia associated with this syndrome could lead to diminished apoptotic cell death during brain development leading to increased cell packing density, and additional roles could be played by abnormal elastin development or related molecules (e.g., laminin) involved in neuronal migration and guidance and neurite outgrowth and survival. It is important to determine the status of developmental cell death in WMS as well as expression of molecules implicated by genetic research. We have preliminary results on a second WMS brain and we expect to get at least three additional ones in the three years of the grant for detailed anatomical studies. We have contacts with the NIH sponsored National Brain Bank, to optimize harvesting opportunities. The brain specimens, compared to appropriate age- and sex-matched controls should provide us with information regarding the nature of architectonic and histological changes, topography of changes, severity and extent according to topography, status of specific neuronal and glial markers involved in cortical development and related to the genetic pathology, incidence and type of developmental changes, incidence and type of neuropathologic changes relating to acquired brain disease, and clues as to possible mechanisms for brain change in WMS. Brains will be collected for standard neuropathologic, architectonic, and morphometric studies. A ny alteration in cortical nd subcortical development will be noted. Appropriate sections will undergo semiautomated image processing for cell size and cell numbers. A qualitative assessment of immunostaining for a range of appropriate neuronal and glial elements will be carried out. Limited amount of Golgi impregnation for detailed morphology may also be carried out. It is expected that 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 development.
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