Article

Metabotropic glutamate receptors and fragile x mental retardation protein: Partners in translational regulation at the synapse

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Science Signaling (Impact Factor: 7.65). 02/2008; 1(5):pe6. DOI: 10.1126/stke.15pe6
Source: PubMed

ABSTRACT Fragile X syndrome (FXS) mental retardation is caused by loss-of-function mutations in an RNA-binding protein, fragile X mental retardation protein (FMRP). Previous studies in patients or animal models of FXS have identified alterations in dendritic spine structure, as well as synaptic plasticity induced by metabotropic glutamate receptors (mGluRs). The translation of multiple messenger RNA (mRNA) targets of FMRP is regulated by mGluRs at synapses. Here, we incorporate data from several studies into a working model of how FMRP regulates mGluR-stimulated protein synthesis and, in turn, regulates protein synthesis-dependent synaptic plasticity. Understanding the complex functions of FMRP at the synapse will lead to a better understanding of the neurobiological underpinnings of mental retardation.

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    • "The expression of APP can be upregulated upon mGluR5 stimulation. FMRP, which is also regulated by mGluR5 (Ronesi and Huber, 2008; Wang et al., 2008a; Wang and Zhuo, 2012), binds to and represses the translation of APP mRNA due to mGluR5 activation (Westmark and Malter, 2007; Westmark, 2013). The mGluR5 links FMRP with APP. "
    Frontiers in Cellular Neuroscience 02/2015; 9:43. DOI:10.3389/fncel.2015.00043 · 4.18 Impact Factor
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    • "As indicated above, these and the present data may be related to the need for a balance between the modulation of LTP and LTD by mGluR5 receptors (Neyman and Manahan-Vaughan 2008; Ayala et al. 2009; Dölen et al. 2010; Millan et al. 2012). From a pathological perspective, and consistent with the present data, modest doses of mGluR5 agonists would promote cognition by normalising deficits in mGluR5 (and NMDA) receptor signalling seen in (the frontal cortex) in schizophrenia, whereas antagonists would be required to counter the over-stimulation of mGluR5 receptors (in hippocampus and amygdala) seen in Fragile X (Palmer et al. 1997; Ronesi and Huber 2008; Dölen et al. 2010; Stefani and Moghaddam 2010; Horio et al. 2012; Won et al. 2012; Millan et al. 2012; Zoghbi and Bear 2012). Finally, in this light, it should be noted that CDPPB and ADX47273 are highly selective ligands (Kinney et al. 2005; Liu et al. 2008) and the specificity of the enhancement of SND by mGluR5 PAMs Fig. 8 CDPPB and ADX47273 reverse a social novelty discrimination deficit induced by the neonatal administration of PCP, in the pharmacological deficit protocol. "
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    ABSTRACT: Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.
    Psychopharmacology 09/2012; DOI:10.1007/s00213-012-2845-3 · 3.99 Impact Factor
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    • "In contrast, whether a particular spine density phenotype is apparent in the mouse model does depend on the brain region being examined (Fig. 1). Given the wellestablished deficits in mGluR-dependent LTD in the hippocampus of Fmr1 KO mice (reviewed by Ronesi and Huber, 2008) and the important role of this region in learning and memory, investigators have also looked for spine alterations in hippocampal pyramidal neurons. Spine density changes appear to be especially variable in the hippocampus, where studies of Fmr1 KO mice have found either normal (Pfeiffer and Huber, 2007; de Vrij et al., 2008; Levenga et al., 2011b; Su et al., 2011), higher (Antar et al., 2006; Grossman et al., 2006; Gross et al., 2010; Levenga et al., 2011a; Swanger, 2011), or even lower spine densities (Braun and Segal, 2000; Segal et al., 2003). "
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    ABSTRACT: Dendritic spines are the principal recipients of excitatory synaptic inputs and the basic units of neural computation in the mammalian brain. Alterations in the density, size, shape, and turnover of mature spines, or defects in how spines are generated and establish synapses during brain development, could all result in neuronal dysfunction and lead to cognitive and/or behavioral impairments. That spines are abnormal in fragile X syndrome (FXS) and in the best-studied animal model of this disorder, the Fmr1 knockout mouse, is an undeniable fact. But the trouble with spines in FXS is that the exact nature of their defect is still controversial. Here, we argue that the most consistent abnormality of spines in FXS may be a subtle defect in activity-dependent spine plasticity and maturation. We also propose some future directions for research into spine plasticity in FXS at the cellular and ultrastructural levels that could help solve a two-decade-long riddle about the integrity of synapses in this prototypical neurodevelopmental disorder.
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