Local Protein Synthesis and Spine Morphogenesis: Fragile X Syndrome and Beyond

Department of Psychology, University of Illinois, Urbana-Champaign, Urbana, Illinois, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2006; 26(27):7151-5. DOI: 10.1523/JNEUROSCI.1790-06.2006
Source: PubMed


Behavioral experiences can modulate neural networks through changes in synaptic morphology and number. In contrast, abnormal morphogenesis of dendritic spines is associated with cognitive impairment, as in Fragile X syndrome. Dendritic or synaptic protein synthesis could provide the specificity and speed necessary for spine morphogenesis. Here, we highlight locally translated proteins shown to affect synaptic morphology (e.g., Fragile X mental retardation protein).

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    • "Bryostain-1 was administered at a dose at which it promotes learning-induced synaptogenesis and synaptic maturation (Hongpaisan and Alkon 2007, Hongpaisan et al., 2011). Mice lacking expression of FMR1 show an abundance of dense, immature dendritic spines (Scotto-Lomassese et al., 2011), as in FXS patients (Grossman et al., 2006). The hyperabundance of immature-looking lengthened dendritic spines could be the results of a failed/delayed maturation (Cruz-Martin et al., 2010; Harlow et al., 2010) and activity-dependent synaptic elimination (Pfeiffer et al., 2010). "
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    ABSTRACT: Fragile X syndrome (FXS) is caused by transcriptional silencing in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP), a repressor of dendritic mRNA translation. The lack of FMRP leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, a disorder which currently has no effective therapeutics. Fragile X mice were treated with chronic bryostatin-1, a relatively selective PKCε activator with pharmacological profiles of a rapid mGluR desensitization, synaptogenesis, and synaptic maturation/repairing. Differences in the major FXS phenotypes, synapses, and cognitive functions were evaluated and compared among the age-matched groups. Chronic treatment with bryostatin-1 rescues adult fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in hippocampal brain-derived neurotrophic factor (BDNF) expression and secretion, PSD-95 levels, GSK-3β phosphorylation, transformation of immature dendritic spines to mature synapses, densities of the presynaptic and postsynaptic membranes, and spatial learning and memory. Our results show that synaptic and cognitive function of adult FXS mice can be normalized through pharmacological treatment and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation even after postpartum brain development has largely completed.
    Full-text · Article · Mar 2014 · Journal of Pharmacology and Experimental Therapeutics
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    • "The current concept is that absence of FMRP induces translation dysregulation and defects in mRNA transport that are thought to alter local protein synthesis essential for synaptic development and maturation [3], [10]–[12]. One of the consequences of the lack of FMRP is the presence of abnormal looking immature and supernumerary neuronal dendritic spines in the brains of fragile X patients [13], [14], that ultimately lead to mental retardation in FXS patients. "
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    ABSTRACT: Fragile X syndrome is caused by the absence of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein. FMRP is associated with messenger RiboNucleoParticles (mRNPs) present in polyribosomes and its absence in neurons leads to alteration in synaptic plasticity as a result of translation regulation defects. The molecular mechanisms by which FMRP plays a role in translation regulation remain elusive. Using immunoprecipitation approaches with monoclonal Ab7G1-1 and a new generation of chicken antibodies, we identified Caprin1 as a novel FMRP-cellular partner. In vivo and in vitro evidence show that Caprin1 interacts with FMRP at the level of the translation machinery as well as in trafficking neuronal granules. As an RNA-binding protein, Caprin1 has in common with FMRP at least two RNA targets that have been identified as CaMKIIα and Map1b mRNAs. In view of the new concept that FMRP species bind to RNA regardless of known structural motifs, we propose that protein interactors might modulate FMRP functions.
    Full-text · Article · Sep 2012 · PLoS ONE
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    • "It has been suggested that neurological and psychiatric symptoms associated with FraX may be a consequence of an exaggerated response to metabotrophic glutamate receptor (mGluR) activation due to an absence/reduction of FMRP [36]. FMRP modulates dendritic maturation and synaptic plasticity and one of the mechanisms postulated for this effect is its inhibition of the metabotrophic Glu receptors (mGluR), mGluR1 and mGluR5 mediated mRNA translation in dendrites [37,38]. In mouse models the mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP) has been shown to reverse behavioral phenotypes (including hyperactivity, seizures, pre-pulse inhibition deficits, repetitive behaviors) and to lead to remarkable improvements in synaptic plasticity and spine morphology [39]. "
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    ABSTRACT: There is increasing evidence that neurodevelopmental differences in people with Fragile X syndrome (FraX) may be explained by differences in glutamatergic metabolism. Premutation carriers of FraX were originally considered to be unaffected although several recent reports demonstrate neuroanatomical, cognitive, and emotional differences from controls. However there are few studies on brain metabolism in premutation carriers of FraX. We used proton magnetic resonance spectroscopy to compare neuronal integrity of a number of brain metabolites including N-Acetyl Aspartate, Creatine + Phosphocreatinine, Choline, myoInositol, and Glutamate containing substances (Glx) in 17 male premutation carriers of FraX and 16 male healthy control individuals. There was no significant between-group difference in the concentration of any measured brain metabolites. However there was a differential increase in N-acetyl aspartate with aging in premutation FraX individuals compared to controls. This is the first 1 H-MRS study to examine premutation FraX individuals. Although we demonstrated no difference in the concentration of any of the metabolites examined between the groups, this may be due to the large age ranges included in the two samples. The differential increase in NAA levels with aging may reflect an abnormal synaptic pruning process.
    Full-text · Article · Aug 2012 · Journal of Neurodevelopmental Disorders
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