We recently obtained evidence in an in vitro synaptoneurosome preparation for the rapid translation of the mRNA at the synapse, under metabotropic glutamate receptor control. We also have found that """"""""knockout"""""""" mice that cannot produce this protein exhibit immature synapse morphology and produce or retain excess numbers of spine synapses into adulthood. Our preliminary data indicates regulation of cortical FMRP expression by motor skill training in adult rats. These findings complete other work on the fragile X gene (FMR1) and syndrome (FraXS) to suggest as a """"""""working hypothesis"""""""" that FMRP may play a role in the process whereby synaptic activity during development results in structural maturation of the synapse, and may be necessary for the normal developmental synapse elimination process. We process a series of basic studies of rodent brain designed to further explore 1) the cellular and subcellular localization of FMRP with regard to both macro (soma, dendrite) and micro (organelle) structures, as a further source of clues to the possible cellular function of the protein, 2) the spatiotemporal pattern of expression during development and it is possible correlation with other major developmental processes such as synaptogenesis, to explore possible reasons for the pathological effects of fragile X deficiencies on brain development, 3) the effects of electrical stimulation of axonal pathways on its expression in target neurons to determine if it us under synaptic control in vivo, and 4) the effects of behavioral experience, ranging from monocular visual deprivation to complex rearing environments and motor skill learning upon its expression in brain regions known to exhibit plasticity in response to those manipulations. We also response to examine 5) development and adult morphology, 6) effects of experience, and 7) the elimination of multiple innervation of Purkinje cells by climbing fibers in a recently developed transgenic fragile X knockout mouse. Fragile X syndrome, which can arise from a mutations that prevents gene expression or from point mutations affecting the structure of the protein, is the leading inherited cause of human mental retardation and is also frequently associated with Autism and Attentional Deficit/Hyperactivity Disorder. Knowledge of the mechanism of action of the gene product may well give rise to treatments of these syndromes.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1-BDCN-5 (01))
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Oster-Granite, Mary Lou
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University of Illinois Urbana-Champaign
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Galvez, Roberto; Greenough, William T (2005) Sequence of abnormal dendritic spine development in primary somatosensory cortex of a mouse model of the fragile X mental retardation syndrome. Am J Med Genet A 135:155-60
Galvez, Roberto; Smith, Rebecca Lynn; Greenough, William T (2005) Olfactory bulb mitral cell dendritic pruning abnormalities in a mouse model of the Fragile-X mental retardation syndrome: further support for FMRP's involvement in dendritic development. Brain Res Dev Brain Res 157:214-6
McKinney, Brandon C; Grossman, Aaron W; Elisseou, Nicholas M et al. (2005) Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout mice. Am J Med Genet B Neuropsychiatr Genet 136B:98-102
Irwin, Scott A; Christmon, Chariya A; Grossman, Aaron W et al. (2005) Fragile X mental retardation protein levels increase following complex environment exposure in rat brain regions undergoing active synaptogenesis. Neurobiol Learn Mem 83:180-7
Weiler, Ivan Jeanne; Spangler, Chad C; Klintsova, Anna Y et al. (2004) Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses. Proc Natl Acad Sci U S A 101:17504-9
Grossman, Aaron W; Churchill, James D; McKinney, Brandon C et al. (2003) Experience effects on brain development: possible contributions to psychopathology. J Child Psychol Psychiatry 44:33-63
Miyashiro, Kevin Y; Beckel-Mitchener, Andrea; Purk, T Patrick et al. (2003) RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37:417-31
Galvez, Roberto; Gopal, Anjali R; Greenough, William T (2003) Somatosensory cortical barrel dendritic abnormalities in a mouse model of the fragile X mental retardation syndrome. Brain Res 971:83-9
Angenstein, Frank; Evans, Anne M; Settlage, Robert E et al. (2002) A receptor for activated C kinase is part of messenger ribonucleoprotein complexes associated with polyA-mRNAs in neurons. J Neurosci 22:8827-37
Churchill, James D; Grossman, Aaron W; Irwin, Scott A et al. (2002) A converging-methods approach to fragile X syndrome. Dev Psychobiol 40:323-38

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