Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses

Antar, Laura N.; Li, Chanxia; Zhang, Honglai; Carroll, Reed C.; Bassell, Gary J.

doi:10.1016/j.mcn.2006.02.001

Cited by 232 publications

(282 citation statements)

References 40 publications

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“…One study has even described fewer protrusions in hippocampal cultures of Fmr1 KO mice (Braun 2000). Another more recent study showed increased density of filopodia-like spines in cultured Fmr1 KO hippocampal neurons, but with many more protrusions per distance (3-5 filopodia/ 10 μm) than in our study (Antar et al, 2006). However, these cultures were not fully matured and different culture methods (such as use of glial cell feeder layers) might influence the protrusion number.…”

Section: Discussioncontrasting

confidence: 80%

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

Vrij

Levenga

Linde

et al. 2008

Neurobiology of Disease

293

250

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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.

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Section: Discussioncontrasting

confidence: 80%

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

Vrij

Levenga

Linde

et al. 2008

Neurobiology of Disease

293

250

View full text Add to dashboard Cite

show abstract

“…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: 75%

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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“…(1) The Drosophila orthologs of FMRP (dFXR) and its interacting proteins play essential roles in axon growth and neuronal connectivity (Morales et al, 2002;Schenck et al, 2003;Pan et al, 2004). (2) FMRP is present in axons and growth cones of hippocampal neurons, and the regulation of axonal growth is altered in hippocampal neurons from Fmr1 KO mice (Antar et al, 2005(Antar et al, , 2006.…”

Section: Discussionmentioning

confidence: 99%

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

Hanson¹,

Madison²

2007

J. Neurosci.

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Almost all female and some male fragile X syndrome (FXS) patients are mosaic for expression of the FMR1 gene, yet all research in models of FXS has been in animals uniformly lacking Fmr1 expression. Therefore, we developed a system allowing neuronal genotype to be visualized in vitro in mouse brain slices mosaic for Fmr1 expression. Whole-cell recordings from individual pairs of presynaptic and postsynaptic neurons in organotypic hippocampal slices were used to probe the cell-autonomous effects of Fmr1 genotype in mosaic networks. These recordings revealed that wild-type presynaptic neurons formed synaptic connections at a greater rate than presynaptic neurons lacking normal Fmr1 function in mosaic networks. At the same time, the postsynaptic Fmr1 genotype did not influence the probability that a neuron received synaptic connections. Asymmetric presynaptic function during development of the brain could result in a decreased participation in network function by the portion of neurons lacking FMR1 expression.

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Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses

Cited by 232 publications

References 40 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

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

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

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