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Download 2006 natl fx fnd abstract - University of Illinois Archives
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Architecture of spines and dendrites in fragile X syndrome: An overview. William T. Greenough, Ph.D., Roberto Galvez, Ph.D., Aaron W. Grossman, B.A., Scott A. Irwin, M.D. Ph.D., Brandon C. McKinney, M.S., Im Joo Rhyu M.D. Ph.D., Georgina M. Aldridge, B.S., Julie A. Markham, Ph.D. Bill, you’ve got 1 word to spare. I pasted your old version below so if I dropped any important ideas you can try to put them back. Good luck! Also, do you mind if my name goes before Robert’s? 350 word / 3500 character limit In studies of Fragile X syndrome (FXS) and Fmr1 knockout mice, a model for FXS, a consistent finding has been pathology of dendritic spines, the post-synaptic target of excitatory inputs. Increasing evidence indicates that the "wiring diagram" of the Fragile X brain is profoundly disordered, and understanding how such disorder arises may be important for developing treatments. The neocortex of patients with FXS is characterized by an excess of dendritic spines, many of which tend to be longer and thinner than those in unaffected individuals. Spines in the Fmr1 knockout mouse neocortex have a similar phenotype that appears to arise through abnormalities in spine maturation and in the developmental "pruning" process that eliminates inappropriate connections. Fmr1 knockout mice also exhibit abnormal pruning of dendrites in neurons of the somatosensory cortex and olfactory bulb. Thus the “wiring diagram” of these brain regions may be generated by a combination of impaired pruning and impaired modification of synapses. We subsequently examined the hippocampal formation, where the pattern of development is somewhat different from that of the cerebral cortex. In area CA1, the profile of spine shapes in Fmr1 knockouts is abnormal compared with the spine shape profile of wildtype mice, and seems to reflect the profile seen in area CA1 of younger animals. In addition, spines of each shape are longer in knockout CA1 than in controls. Spines in the dentate gyrus also appear to develop abnormally. For example, the density of spines along these dendrites appears elevated across development, suggesting that no pruning deficit exists in this brain region. As a clearer picture of Fragile X neuropathology emerges, we find that some measures differ by brain region (presence or absence of pruning) whereas other measures are observed across several brain regions (increased spine length and density). Spine maturation and plasticity may therefore be regulated in each brain region by different mechanisms, some of which require FMRP (absent in Fragile X syndrome) and its mRNA cargos, and others for which FMRP is less important. Brain organization in FXS likely involves the convergence of these mechanisms, providing a context in which development unfolds. 1. To illustrate progress in understanding the mechanisms behind the changes in brain structure that occur in fragile X syndrome 2. To illustrate that common principles underlie brain development in fragile X and unaffected individuals 3. To present this work at a level that will speak to scientists and yet be understood by parents and family members 4. To illustrate the value of basic research using animal models of fragile X syndrome in developing criteria that can be used to evaluate the potential effects of treatments. Old version Increasing evidence indicates that the "wiring diagram" of the nervous system in Fragile X syndrome is seriously disordered, beyond the level of mere differential strength of synapses (e.g., Kogan et al., Neurology 2004, 63:1634-39). Understanding how such disorder arises may be important to developing treatments. The cerebral cortex in FXS is characterized by an excess of spines, the post-synaptic target of most excitatory inputs, onto principal neurons. The FXS spines also tend to be longer and thinner than those in unaffected individuals. The knockout (KO) mouse model for FXS similarly has an excess of spines overall and an excess of long, thin spines on cerebral cortical neurons. These differences may arise through abnormalities in the developmental "pruning" process that eliminates unused or inappropriate connections. Evidence for this includes abnormal dendritic pruning in "barrel" neurons of the somatosensory cortex, and in mitral cells of the olfactory bulb in the KO mouse. In addition, the pruning of spines seen in development of the somatosensory cortex in normal mice is not evident in the KO mouse. Thus for cerebral cortex (and olfactory bulb) the neural phenotype seems to be generated by a combination of pruning and of modification of synapses. We have subsequently examined the hippoccampal formation in which the pattern of development is somewhat different from that of the cerebral cortex but appears to follow a broad set of common rules of development. Thus subfield CA1 (or hippocampus proper) [Aaron, could you fill in a relatively simple statement here?] Our preliminary results for hippocampal dentate gyrus indicateŠ. This pattern of different patterns in some measures across brain regions (e.g., presence or absence of pruning) and similarities in other measures (increased spine density; increased spine length) suggests that brain organization in FXS may involve a combination of Fmr1-independent local determinants that provide a context in which development unfolds and Fmr1-dependent global determinants that may reflect specific influences of the fragile X gene or of its mRNA cargoes that are disrupted in common across brain regions]