FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK Channels

Deng, Pan; Rotman, Ziv; Blundon, Jay A.; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S.; Klyachko, Vitaly A.

doi:10.1016/j.neuron.2012.12.018

Cited by 310 publications

(354 citation statements)

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“…One intriguing possibility is that FXGs are associated with ion channels, since FMRP directly binds to ion channels and modulates their function in axons (11,(44)(45)(46). These findings suggest a model in which FXGs constitutively associate with channels while mRNAs transition between FXG and non-FXG complexes in response to signalling events.…”

Section: Dynamic Association Of Rna With Fxgsmentioning

confidence: 99%

“…Sections were then rinsed twice for 1 min each in PBS before a 10-min equilibration in 2X SSC þ 10% formamide. Sections were exposed overnight at 37 C to hybridization solution (10% dextran sulphate, 1 mg/ml E. coli tRNA, 2 mM Vanadyl Ribonucleoside, 200 lg/ml BSA, 2X SSC, 10% deionized formamide) containing 80 nM oligo(dT) 45 that had been end-labelled with DIG Oligonucleotide Tailing Kit, 2nd generation (Roche) following the included instructions for short tails. On the second day, the slides were washed two times for 30', each at 37 C in 2X SSC þ 10% formamide, and then rinsed briefly in 2X SSC followed by a rinse in PBST.…”

Section: Immunofluorescence On Human Tissuementioning

confidence: 99%

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Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

et al. 2017

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Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXGassociated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life.

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Section: Dynamic Association Of Rna With Fxgsmentioning

confidence: 99%

Section: Immunofluorescence On Human Tissuementioning

confidence: 99%

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

et al. 2017

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“…In mosaic Fmr1 mice, the presynaptic presence of FMRP is sufficient to rescue synaptic connectivity defects in the hippocampal circuit (16), and in Aplysia, down-regulation of FMRP in presynaptic neurons is sufficient to enhance long-term synaptic depression (17). Furthermore, FMRP regulation of neurotransmitter release at excitatory hippocampal and cortical synapses has been shown to be a cell-autonomous presynaptic and translation-independent process (18,19).Both the pre-and postsynaptic functions of FMRP have also been linked to neuronal and circuit hyperexcitability in FXS animal models. Consistent with its role as a protein synthesis regulator, FMRP regulates the expression of a number of dendritic voltage-gated K + channels in various brain circuits (20)(21)(22).…”

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confidence: 99%

mentioning

confidence: 99%

“…FMRP also modulates activity of the large-conductance calcium-activated potassium (BK) channel in hippocampal and cortical excitatory neurons, which is critical for controlling action potential (AP) duration and neurotransmitter release (18). FMRP interacts with the regulatory β4-subunit of the BK channel to increase channel Ca 2+ sensitivity and limit AP duration and neurotransmitter release.…”

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Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

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

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Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre-and postsynaptic defects, yet whether the pre-and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic-and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.F ragile X syndrome (FXS) is the most common single-gene disorder responsible for intellectual disability (ID) in patients (1). Along with cognitive dysfunction, the syndrome typically presents with several other comorbidities, including behavioral and social impairments (anxiety and autism spectrum disorder), neurological defects (seizures and abnormal sleep patterns), and morphological abnormalities (dysmorphic facies and macroorchidism). Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP.FMRP has complex multifaceted functions at synapses both in pre-and postsynaptic compartments. As an RNA binding protein, FMRP is best known for its function as a translation regulator in dendrites (2). Loss of FMRP has been linked to various forms of long-term synaptic plasticity defects that depend on local protein synthesis in the postsynaptic neuron (3). In addition to disrupted metabotropic glutamate receptor signaling, which has been shown across multiple brain regions (4-7), FMRP is necessary for activitydependent protein synthesis downstream of other signaling receptor pathways, including ACh, dopamine, and TrkB (8-10).Although postsynaptic control of translation is believed to be the dominant function of FMRP, it is unable to explain all of the pathophysiology observed in FXS animal models. For instance, in Drosophila, presynaptic expression of the FMR1 homolog, dfmr1, completely rescues the synaptic overgrowth phenotype at the neuromuscular junction (NMJ) in dfmr1-null mutants (11-13). In rodent brain, FMRP has been found in structures called fragile-X granules, which are ...

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High functioning male with fragile X syndrome and fragile X‐associated tremor/ataxia syndrome

Basuta¹,

Schneider

Gane

et al. 2015

American J of Med Genetics Pt A

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Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS.

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FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK Channels

Cited by 310 publications

References 39 publications

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

High functioning male with fragile X syndrome and fragile X‐associated tremor/ataxia syndrome

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