Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors

Nakamoto, Mika; Nalavadi, Vijayalaxmi; Epstein, Michael P.; Narayanan, Usha; Bassell, Gary J.; Warren, Stephen T.

doi:10.1073/pnas.0707484104

Cited by 224 publications

(190 citation statements)

References 38 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…Since spine shape is correlated with the number of AMPA receptors in the postsynaptic density (Matsuzaki et al, 2001), these data correlate with the rescue effect of MPEP on AMPA receptor trafficking as shown by Nakamoto et al (Nakamoto et al, 2007). In the latter study, the concentrations of MPEP used on primary neurons (10-50 μM) differed from our experiments due to different time courses of the experiments.…”

Section: Discussioncontrasting

confidence: 52%

“…The mGluR theory states that AMPA receptor internalization triggered by mGluR5 stimulation (Snyder et al, 2001), is exaggerated in Fmr1 KO mice, accounting for the enhanced hippocampal LTD found in knockout mice (Bear et al, 2004;Huber et al, 2002). Recently it was shown that FMRP deficient dendrites indeed show aberrant AMPA receptor trafficking resulting in a significantly reduced number of AMPA receptors at the plasma membrane (Nakamoto et al, 2007). Moreover, Fmr1 KO mice that are crossbred with mice that have a 50% reduction in mGluR5 expression were shown to be rescued in several phenotypic aspects (Dolen et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

Vrij

Levenga

Linde

et al. 2008

Neurobiology of Disease

296

250

View full text Add to dashboard Cite

Lack of fragile X mental retardation protein (FMRP) causes Fragile X Syndrome, the most common form of inherited mental retardation. FMRP is an RNA-binding protein and is a component of messenger ribonucleoprotein complexes, associated with brain polyribosomes, including dendritic polysomes. FMRP is therefore thought to be involved in translational control of specific mRNAs at synaptic sites. In mice lacking FMRP, protein synthesis-dependent synaptic plasticity is altered and structural malformations of dendritic protrusions occur. One hypothesized cause of the disease mechanism is based on exaggerated group I mGluR receptor activation. In this study, we examined the effect of the mGluR5 antagonist MPEP on Fragile X related behavior in Fmr1 KO mice. Our results demonstrate a clear defect in prepulse inhibition of startle in Fmr1 KO mice, that could be rescued by MPEP. Moreover, we show for the first time a structural rescue of Fragile X related protrusion morphology with two independent mGluR5 antagonists.

show abstract

Section: Discussioncontrasting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

Vrij

Levenga

Linde

et al. 2008

Neurobiology of Disease

296

250

View full text Add to dashboard Cite

show abstract

“…This mechanism appears to be compromised in FXS, because reduced levels of FMRP were shown to lead to increased mGlu 5 -mediated GluA endocytosis in rat hippocampal neurons (Nakamoto et al, 2007). The mGlu 1/5 -dependent translational induction of two FMRP targets, Arc/Arg3.1 and MAP1B, which were suggested to be involved in activity-regulated GluA endocytosis in hippocampal neurons (Davidkova and Carroll, 2007;Waung et al, 2008), is absent in Fmr1 KO mice Park et al, 2008).…”

Section: Increased and Protein Synthesis-independent Mglu 1/5 Ltd In Fxsmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

show abstract

“…One of the major findings leading to the mGluR theory is that in the hippocampus the group 1 mGluR receptor, mGluR5, is involved in long-term depression (LTD), a form of synaptic plasticity that is enhanced in the Fmr1 knockout (Fmr1 KO) mouse (4,5). The underlying basis for this enhanced hippocampal mGluR-LTD is abnormally high internalization of the AMPA receptor (AMPAR) subunit, GluR1, caused by the absence of the endpoint inhibition normally provided by FMRP (2,6). Interestingly, defective AMPAR-mediated plasticity has also emerged as a common phenotype in other brain areas in the Fmr1 KO mouse, including the cortex and cerebellum (7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome

Suvrathan

Hoeffer

Wong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

108

View full text Add to dashboard Cite

Fragile X syndrome (FXS), a common inherited form of mental impairment and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. Earlier studies have identified a role for aberrant synaptic plasticity mediated by the metabotropic glutamate receptors (mGluRs) in FXS. However, many of these observations are derived primarily from studies in the hippocampus. The strong emotional symptoms of FXS, on the other hand, are likely to involve the amygdala. Unfortunately, little is known about how exactly FXS affects synaptic function in the amygdala. Here, using whole-cell recordings in brain slices from adult Fmr1 knockout mice, we find mGluR-dependent long-term potentiation to be impaired at thalamic inputs to principal neurons in the lateral amygdala. Consistent with this long-term potentiation deficit, surface expression of the AMPA receptor subunit, GluR1, is reduced in the lateral amygdala of knockout mice. In addition to these postsynaptic deficits, lower presynaptic release was manifested by a decrease in the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), increased pairedpulse ratio, and slower use-dependent block of NMDA receptor currents. Strikingly, pharmacological inactivation of mGluR5 with 2-methyl-6-phenylethynyl-pyridine (MPEP) fails to rescue either the deficit in long-term potentiation or surface GluR1. However, the same acute MPEP treatment reverses the decrease in mEPSC frequency, a finding of potential therapeutic relevance. Therefore, our results suggest that synaptic defects in the amygdala of knockout mice are still amenable to pharmacological interventions against mGluR5, albeit in a manner not envisioned in the original hippocampal framework.autism | long-term potentiation | synaptic plasticity | metabotropic glutamate receptor

show abstract

Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors

Cited by 224 publications

References 38 publications

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome

Contact Info

Product

Resources

About