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Cellular Substrates of Fragile X Syndrome

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Session 3: Molecular Genetics of Autism

William T. Greenough1, Ivan Jeanne Weiler1, James H. Eberwine*, Scott Irwin1, Roberto Galvez1, and James Churchill1,
1Departments of Psychology, Psychiatry and Cell and Structural Biology, Neuroscience Program and Beckman Institute University of Illinois at Urbana-Champaign; *Department of Pharmacology, University of Pennsylvania Medical Center.

A recent report indicates that autistic symptoms exhibited by Fragile X syndrome (FXS) cases are indistinguishable from those of non-FXS autistic cases (Rogers et al., in press). Hence knowledge of FXS may shed light on substrates of autism. In FXS, a protein, FMRP, is not produced due to suppression of transcription of the FMR1 gene. We have found that FMRP is normally synthesized at the synapse and that a knockout mouse that cannot produce FMRP cannot synthesize certain other proteins, at least in normal amounts, at the synapse in response to glutamate receptor activation. The implication is that symptoms of FXS (and potentially of autism) may arise from inadequate synthesis of a group of synaptic proteins. We are trying to determine what proteins are differentially expressed in the knockout mouse. In studying synapse morphology, we find, both in human autopsy cases and in the knockout mouse that spines, the receiving part of the synapse through which neurons communicate, exhibit an immature form. In the human cases, there is also an increase in the density of spines. Our interpretation of these results is that the FMR gene is necessary for neural maturation, which involves both the development of an adult-like synaptic structure and the loss of "unneeded" synapses. Examination of dendritic development in the somatosensory whisker barrel model has confirmed that neural pruning is impaired in FXS. Our tentative conclusion is that FMRP may control some aspects of synaptic protein synthesis that are essential to the maturation of neurons and likely plays a significant role in later plastic brain processes as well. Supported by HD37175, AG9900, MH11272, HD07333 and FRAXA Res. Fndn.

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Last Reviewed: 11/30/2012
Vision National Institutes of Health Home BOND National Institues of Health Home Home Storz Lab: Section on Environmental Gene Regulation Home Machner Lab: Unit on Microbial Pathogenesis Home Division of Intramural Population Health Research Home Bonifacino Lab: Section on Intracellular Protein Trafficking Home Lilly Lab: Section on Gamete Development Home Lippincott-Schwartz Lab: Section on Organelle Biology