The development and interfacing of neuropsychological testing in mice and humans to advance gene investigations into WBS

Genetic approaches currently available in the mouse make this organism powerful for functional analysis of important genes and for defining molecular pathways underlying the pathogenesis of human disease. By ?engineering? mice to carry the same genetic defects as human patients we can study the resulting neurological and behavioural impairments in ways not possible in humans. But some subtle effects may be missed because current mouse tests may not assess the correct behavioural domains. Indeed human/mouse comparisons are often impossible because the tasks used are completely different. The pathological role of key genes are then missed and may be excluded from investigations into brain development. Individuals with Williams syndrome display problems in motor actions, anxiety, social behaviour, learning and memory, but the separate contributions from the different genes known to be involved are unknown. By developing tasks as similar as possible to those impaired in the patients and testing mice carrying mutations in specific Williams syndrome genes, we can investigate the separate contributions from each gene. The resulting comparisons will help us understand exactly what is going wrong in the patients, and may give clues to eventual remediation methods.

We propose to develop a framework that will maximize the ability of targeted mouse models to elucidate the genetic and molecular mechanisms that regulate normal and abnormal biological processes underlying human behaviour and cognition in Williams-Beuren syndrome (WBS). Elucidation of gene function often involves cross-species comparisons of tasks requiring different cognitive demands, e.g. object-oriented space in humans compared to navigational space in animals. These two aspects of spatial cognition are known to dissociate in neuropsychological patients and therefore must call on different cognitive processes. We will analyze the key task demands of a battery of existing tests for humans and for mice, and then create for each species tasks based on paradigms that show deficits in WBS patients which render comparisons equivalent at the cognitive level. The discovery of associations between neurological development and candidate genes offers the prospect of characterising deficits in WBS patients and instituting educational and lifestyle measures to guide their developmental progression, as well as advancing functional investigations into the biological role of critical genes in WBS aetiology. The discovery of associations between neurological development and certain candidate genes offers the prospect of not only characterising deficits in WBS individuals and instituting educational and lifestyle measures to guide their developmental progression, but also advancing functional investigations into the role of the GTF family of transcription factors and CYLN2, all highly expressed in the brain and implicated in the WBS phenotype, in the aetiology of this neurological disorder. By initially studying monogenic deletions we can establish their neurological consequences in isolation before attempting investigations into combinatory effects. In summary, we aim not just to formulate a new battery of tests, but to form a fruitful interaction between molecular, behavioural and cognitive neurosciences in humans and mice to extend the ability of behavioural tests to advance investigations into gene function and human development. This work will provide a framework for behavioural investigations into other mouse models of human neurodevelopmental disorders.