Fragile X Mental Retardation Protein Induces Synapse Loss through Acute Postsynaptic Translational Regulation

Pfeiffer, Brad E.; Huber, Kimberly M.

doi:10.1523/jneurosci.0054-07.2007

Cited by 154 publications

(173 citation statements)

References 65 publications

(108 reference statements)

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“…Interestingly, while lower mEPSC frequency and amplitude were recorded upon reduction of SNAP-25 expression, a significant reduction of mEPSC frequency but not amplitude occurred in neurons in which p140Cap was downregulated. These data suggest that while reduced SNAP-25 levels impact both synaptic number and function, downregulation of p140Cap decreases the number of synapses without having major changes in the function or maturational state of the remaining ones, as already described for other postsynaptic proteins 49,50 . Conversely, the lack of changes in mEPCS frequency or amplitude recorded upon either SNAP-25 or p140Cap over-expression suggests that the morphogenetic role of the two proteins may be not accompanied, at least under acute over-expression conditions, by functional effects.…”

Section: Discussionsupporting

confidence: 76%

SNAP-25 regulates spine formation through postsynaptic binding to p140Cap

et al. 2013

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Synaptosomal-associated protein of 25 kDa (SNAP-25) is a member of the Soluble N-ethylmaleimide-sensitive-factor attachment protein receptors (SNARE) protein family, required for exocytosis of synaptic vesicles and regulation of diverse ion channels. Here, we show that acute reduction of SNAP-25 expression leads to an immature phenotype of dendritic spines that are, consistently, less functional. Conversely, over-expression of SNAP-25 results in an increase in the density of mature, Postsynaptic Density protein 95 (PSD-95)-positive spines. The regulation of spine morphogenesis by SNAP-25 depends on the protein's ability to bind both the plasma membrane and the adaptor protein p140Cap, a key protein regulating actin cytoskeleton and spine formation. We propose that SNAP-25 allows the organization of the molecular apparatus needed for spine formation by recruiting and stabilizing p140Cap.

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Section: Discussionsupporting

confidence: 76%

SNAP-25 regulates spine formation through postsynaptic binding to p140Cap

et al. 2013

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“…Either excess or deficit in the number of synapses can lead to pathology. In the case of FXS, cortical neurons of patients or fmr1 KO mice show postsynaptic spines at increased density and with long-neck morphology, which have been interpreted as defects in synapse maturation or pruning (7)(8)(9)(10). Similar spine effects are reported for ASDs (11).…”

mentioning

confidence: 74%

“…Because FD44 and FD16 prevent the NCS-1/Ric8a interaction (Figs. 1D and 2) and we had previously identified the antagonistic effects of these two proteins on synapse number (19,35), we assayed whether the two drug candidates could reduce synapse number in a pathological condition in which synapses are in excess (10). Fragile X is a convenient case for this assay, because the synaptic phenotype is well-characterized and the genetic origin is conserved (1).…”

Section: Resultsmentioning

confidence: 99%

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Mansilla

Chaves-Sanjuán

Campillo

et al. 2017

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

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The protein complex formed by the Ca 2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure-function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.fragile X syndrome | synapse regulation | NCS-1 | protein-protein interaction inhibitor | X-ray crystallography

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“…For example, the basal level of surface AMPARs is lower in the LA of KO mice, but in the hippocampus earlier results appear to be mixed (6,28). However, both of these studies have relied on acute molecular manipulations in cultured hippocampal neurons that are likely to differ from brain tissue in which disease-induced changes have stabilized over the course of development into adulthood.…”

Section: Discussionmentioning

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.

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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

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Fragile X Mental Retardation Protein Induces Synapse Loss through Acute Postsynaptic Translational Regulation

Cited by 154 publications

References 65 publications

SNAP-25 regulates spine formation through postsynaptic binding to p140Cap

SNAP-25 regulates spine formation through postsynaptic binding to p140Cap

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

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

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