Metabotropic Glutamate Receptors and Fragile X Mental Retardation Protein: Partners in Translational Regulation at the Synapse

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Science Signaling  05 Feb 2008:
Vol. 1, Issue 5, pp. pe6
DOI: 10.1126/stke.15pe6


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.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and a leading genetic cause of autism. FXS is due to transcriptional silencing and loss of an RNA-binding protein, fragile X mental retardation protein (FMRP). In both human patients and the mouse model of FXS [Fmr1 knockout (KO)], cortical neurons have an excess of dendritic spines, as well as thin, long, and perhaps immature spines (1). Because dendritic spines are the point of synaptic contact for excitatory neurons, altered synaptic function may underlie FXS. In support of this idea, multiple studies have reported altered synaptic connectivity and plasticity in the Fmr1 KO mouse and that acute manipulation of FMRP in neurons affects synapse number and function (2, 3). How does loss of an RNA-binding protein, such as FMRP, lead to altered synaptic structure and plasticity, and, in turn, lead to mental retardation? Accumulating data that FMRP regulates protein synthesis locally at synapses and in response to the neurotransmitter glutamate provide vital clues to this question.

Dendrites and their associated synapses, which are remote from the neuron soma, contain all the necessary machinery to synthesize proteins; and dendritic protein synthesis is required for long-term, activity-dependent synaptic plasticity (4). FMRP is associated with polyribosomes throughout neurons, including dendritic spines (5, 6). FMRP is also present in smaller messenger ribonucleoprotein complexes (mRNP) and dendritic "RNA granules." RNA granules, which travel in dendrites on microtubules, are thought to be translationally arrested complexes of ribosomes, RNA-binding proteins, and RNAs (7, 8). FMRP may shuttle between the mRNP and polyribosomes depending on the translational state of the cell (9, 10). Currently, data to support a role for FMRP in mRNA transport into dendrites are lacking. Instead, a number of studies implicate FMRP in translational regulation of dendritic mRNAs and, specifically, in response to the action of the neurotransmitter glutamate on certain metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5. MGluR1 and 5, together known as the group 1 mGluRs, are coupled with the family of G protein α subunits, Gq, that controls the activity of phosphatidylinositol-specific phospholipases.

Fmr1 mRNA itself is expressed in dendrites and is bound by FMRP. In addition to Fmr1, other dendritically localized mRNAs, such as those of microtubule-associated protein 1b (MAP1b), postsynaptic density protein of 95 kD (PSD-95), elongation factor 1α (EF1α), and amyloid precursor protein (APP), are FMRP targets, and all are translated in response to mGluR activation (1116). These data suggest that FMRP and mGluRs are functionally linked in regulating translation at synapses. Determining how FMRP regulates translation of its associated mRNAs under basal and mGluR-stimulated conditions will likely be critical to understanding FMRP function in the brain. Evidence from both in vitro translation assays and in vivo studies with Fmr1 KO mice suggests that one function of FMRP is to suppress translation (1719). For example, the brains of Fmr1 KO mice exhibit increased protein synthesis rates and an increased association of dendritic mRNAs, such as those of PSD-95 (a synaptic scaffold), Arc (activity-regulated cytoskeleton-associated protein), and GluR1 (a subunit of the AMPA type of glutamate receptors), with translating polyribosomes in comparison with wild-type mouse brains (14, 15, 17, 20). One proposed mechanism for FMRP-mediated translational suppression is through association with short, noncoding RNAs or microRNAs (miRNAs). These RNAs suppress translation by base-pairing with partially complementary mRNA sequences promoting the interaction with proteins in the RNA-induced silencing complex (RISC). The Argonaut proteins, which are a part of RISC, associate with FMRP, further supporting the idea that FMRP suppresses translation through miRNAs and a RISC-dependent mechanism (21). FMRP-mediated translational suppression of mRNAs in granules is crucial to avoiding inappropriate expression of proteins during transport into dendrites and also may function to increase the stability of certain mRNAs, such as that of PSD-95, in the dendrite. In support of this idea, PSD-95 mRNA stability and hence protein levels are reduced in Fmr1 KO neurons (15).

Once mRNAs reach their dendritic destination, FMRP may also facilitate their translation in response to synaptic activity. Evidence for this hypothesis comes from studies demonstrating that FMRP is mainly associated with translating polyribosomes in brain and that mGluR-stimulated protein synthesis is absent in the Fmr1 KO mice (1, 21). How does FMRP participate in mGluR stimulation of translation? The mGluRs generally activate translation by stimulating a signaling cascade that leads to phosphorylation (and, thus, activation) of translation initiation factors, as well as by stimulating new synthesis of additional translation factors (22). To supply the active translation machinery with mRNA, mGluRs stimulate movement of FMRP and its associated mRNAs into dendrites (6). However, at individual synapses or dendritic spines, there is a dynamic and complex regulation of FMRP by mGluRs. Although mGluRs stimulate FMRP translation, they also cause a rapid ubiquitination and degradation of FMRP, which results in a net decrease in spine FMRP abundance (6, 14). The purpose of the rapid and bidirectional regulation of FMRP by mGluRs is unclear. Perhaps the loss of synaptic FMRP functions to de-repress mRNA targets and allow translation. In addition to regulation of FMRP abundance, posttranslational modifications of FMRP, such as phosphorylation, or recruitment of FMRP from a translationally inactive mRNP or RNA granule to polysomes may "switch" its function from a suppressor to an activator of protein synthesis (10, 23). Consistent with this view, mGluRs activate a protein phosphatase, PP2A, which rapidly dephosphorylates FMRP, and in turn, promotes the translation of an FMRP target mRNA (24). Constitutive loss of FMRP may also alter mGluR function. In Fmr1 KO mice, there is reduced localization of mGluR5 in the postsynaptic density and reduced association of mGluR5 with Homer, a synaptic scaffold and signaling protein, and without the Homer interaction, mGluRs become uncoupled from activation of the translational machinery (25, 26).

Despite the loss of mGluR-stimulated protein synthesis in Fmr1 KO mice, synaptic plasticity that is dependent on mGluR signaling is enhanced, but abnormally regulated in Fmr1 KO mice. Group 1 mGluR activation results in a long-term synaptic depression (LTD) in the hippocampus and cerebellum, which is caused by decreased surface expression of synaptic ionotropic, AMPA-subtype glutamate receptors, which mediate excitatory synaptic transmission. Rapid dendritic protein synthesis is required for both mGluR-mediated LTD and the associated decreases in surface AMPA receptors (AMPARs). In Fmr1 KO mice, mGluR-mediated LTD is enhanced and persists even in the presence of protein synthesis inhibitors (14, 27). Acute knockdown (KD) of FMRP with a small-interfering RNA results in an mGluR5-dependent removal of surface AMPARs (3). One explanation may be that the loss of FMRP and steady-state translational suppression of its mRNA targets results in elevation of a dendritic protein or proteins that stimulate removal of surface AMPARs, but only at synapses in which mGluRs are activated. Therefore, candidate dendritic mRNAs are those known to stimulate endocytosis of AMPARs and to associate with FMRP, such as MAP1b, APP, and Arc (16, 2731) (Fig. 1). Alternatively, decreased stability of PSD-95 mRNA and PSD-95 protein in Fmr1 KO or KD neurons could also lead to decreased abundance of synaptic AMPAR at the cell surface (15, 32). The current challenge is to determine whether the protein expression (or localization or both) of the relevant FMRP target mRNAs is altered in the Fmr1 KO mouse and to determine how this leads to abnormal synapse function and plasticity.

Fig. 1.

Working model of metabotropic glutamate receptor stimulated translation and its regulation by FMRP. (A) FMRP may dually regulate translation of its target mRNAs. At rest (or in unstimulated conditions), FMRP may function as a translational suppressor of target mRNAs, either in an mRNP, RNA granule, or stalled polysome (left). Activation of group 1 mGluRs leads to translation of FMRP target mRNAs, such as those of APP, MAP1b, PSD-95, and perhaps Arc, activation of translation initiation factors, and stimulation of endocytosis of AMPARs (mGluR-dependent processes are shown with green arrows, right). mGluR stimulation results in FMRP ubiquitination and degradation, which may de-repress mRNA targets. Other scenarios, such as FMRP dephosphorylation or movement of FMRP between suppressed granules and translating polysomes, may also contribute to FMRP stimulation of translation. (B) In neurons from Fmr1 KO mice or those in which FMRP is acutely knocked down (KD), loss of translational suppression by FMRP may lead to the association of some FMRP mRNA targets with actively translating polyribomes and increased abundance of the encoded proteins, as well as loss of mGluR-stimulated translation. Other FMRP mRNA targets, such as PSD-95, may be destabilized, which would result in decreased PSD-95 abundance in Fmr1 KO mice. The increased translation of some FMRP targets, such as APP, Arc, and MAP1b, and decreased abundance of PSD-95 would both be expected to lead to decreased surface AMPAR expression, but evidence indicates that these changes in surface AMPARs require mGluR activity.

In addition to altered mGluR-mediated LTD, Fmr1 KO mice appear to have generally enhanced mGluR-mediated plasticity. Group 1 mGluRs trigger persistent bursting of CA3 hippocampal neurons, which is dependent on protein synthesis and can lead to epilepsy. In Fmr1 KO mice, mGluR-dependent epilepsy is enhanced, but unlike mGluR-mediated LTD, still requires protein synthesis (33). Remarkably, reduction of group 1 mGluR activity reduces many symptoms of FXS in animal models, such as epilepsy and learning and memory deficits, which indicates that enhanced functioning of group 1 mGluRs contributes to the etiology of the disease (34, 35). Therefore, the current model places FMRP as a functional "brake" on mGluR- and protein synthesis–dependent plasticity. Recent findings that FMRP similarly regulates LTD and protein synthesis in response to the Gq-coupled M1 muscarinic acetylcholine receptors (mAChRs) suggest that the role of FMRP may extend beyond the mGluRs to multiple Gq-coupled receptors (36).

A model is emerging in which mGluRs dynamically regulate FMRP abundance at the synapse and stimulate local translation of FMRP target mRNAs. Consequently, loss of FMRP, as occurs in FXS, results in altered mGluR-stimulated protein synthesis and protein synthesis–dependent plasticity. However, there are still many unresolved questions with regard to FMRP and the neuronal effects of FMRP loss. Do the alterations in acute synaptic plasticity in Fmr1 KO mice, such as LTD, lead to the observed alterations in dendritic spine number and structure? Or is the latter due to a distinct function of FMRP? As with any knockout-mouse model, it is unclear if the observed effects in Fmr1 KO mice reflect acute functions of FMRP or are a result of constitutive FMRP loss. Despite the large number of FMRP mRNA targets that have been reported, little is known about how their expression and regulation is altered in FXS or if their dysregulation contributes to the FXS phenotype. Resolution of these questions will lead to a better understanding of FMRP in normal brain function and how the loss of FMRP leads to mental retardation and autism.


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