The role of local mRNA translation in the regulation of dendritic spine morphogenesis

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Mental retardation and autism are a highly prevalent and diverse group of disorders for which there is no effective treatment. A common feature of these diseases is that nerve cells from affected patients exhibit abnormally-shaped dendritic spines, structures that serve to form synapses. A critical question in neurodevelopmental disease research is: what causes the abnormal spine morphology in these diseases? Recently, the synthesis of proteins at specific target sites within a cell (“local translation”) has emerged as a novel mechanism for gene regulation that is involved in the control of cell shape and function. In Fragile X syndrome (FXS), the most common form of inherited mental retardation, this mechanism is impaired. Thus, the present project focuses on two questions to explore the role of local translation in the regulation of spine shape: (1) Is the shape of dendritic spines controled by the local translation of a specific regulatory potein (RhoA)? (2) Is this specific regulation impaired in FXS and, thereby, leads to abnormally-shaped spines? In summary, this project might elucidate a novel mechanism for the control of dendritic spine shape and may provide a link between the genetic deficit and the neuroanatomical abnormalities in FXS. Because the regulation of dendritic spine shape has implications for many mental diseases as well as for physiological processes like learning and memory, this project might have a general impact on our understanding of brain function.