FMRP(1–297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome

Zhan, Xiaoqin; Asmara, Hadhimulya; Cheng, Ning; Sahu, Giriraj; Sánchez, Eduardo; Zhang, Fang-Xiong; Zamponi, Gerald W.; Rho, Jong M.; Turner, Ray W.

doi:10.1038/s41467-020-16250-4

Cited by 24 publications

(35 citation statements)

References 56 publications

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“…Future studies must also continue to make use of spatial and temporally restricted deletion of FMR1 to parse the contribution of different cell-types, brain regions, and developmental timepoints to FXS phenotypes. The development of FMRP-tat peptides to reintroduce different FMRP segments to FMR1 KO neurons is a powerful tool for dissociating FMRPs function via direct protein-protein interactions from its canonical role in translational regulation (Zhan et al, 2020 ; Park et al, 2021 ). Finally, the development of novel FXS models—such as the FMR1 KO rat (Till et al, 2015 ; Golden et al, 2019 ; Auerbach et al, 2021 ) and FXS human derived iPS cells (Telias et al, 2013 ; Bhattacharyya and Zhao, 2016 ) and organoids (Kang et al, 2021 ), will help identify which phenotypes are most highly conserved across species and highlight new treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

“…It will be important for future studies to examine both somatic and dendritic excitability in FMR1 KO animals in combination with plasticity levels. A recent study has added another element to these contrary findings by demonstrating that FMRP can also directly interact with Kv4 channels to change their gating properties, resulting in reduced cellular excitability and increased LTP thresholds in cerebellar granule cells (Zhan et al, 2020 ). Importantly, reintroduction of an FMRP fragment that can bind Kv4 into FMR1 KO mice restored deficits in mossy fiber LTP induction and behavioral hyperactivity assessed via open field test (Zhan et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Hyperexcitability and Homeostasis in Fragile X Syndrome

Liu

Kumar

Tsai

et al. 2022

Front. Mol. Neurosci.

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Fragile X Syndrome (FXS) is a leading inherited cause of autism and intellectual disability, resulting from a mutation in the FMR1 gene and subsequent loss of its protein product FMRP. Despite this simple genetic origin, FXS is a phenotypically complex disorder with a range of physical and neurocognitive disruptions. While numerous molecular and cellular pathways are affected by FMRP loss, there is growing evidence that circuit hyperexcitability may be a common convergence point that can account for many of the wide-ranging phenotypes seen in FXS. The mechanisms for hyperexcitability in FXS include alterations to excitatory synaptic function and connectivity, reduced inhibitory neuron activity, as well as changes to ion channel expression and conductance. However, understanding the impact of FMR1 mutation on circuit function is complicated by the inherent plasticity in neural circuits, which display an array of homeostatic mechanisms to maintain activity near set levels. FMRP is also an important regulator of activity-dependent plasticity in the brain, meaning that dysregulated plasticity can be both a cause and consequence of hyperexcitable networks in FXS. This makes it difficult to separate the direct effects of FMR1 mutation from the myriad and pleiotropic compensatory changes associated with it, both of which are likely to contribute to FXS pathophysiology. Here we will: (1) review evidence for hyperexcitability and homeostatic plasticity phenotypes in FXS models, focusing on similarities/differences across brain regions, cell-types, and developmental time points; (2) examine how excitability and plasticity disruptions interact with each other to ultimately contribute to circuit dysfunction in FXS; and (3) discuss how these synaptic and circuit deficits contribute to disease-relevant behavioral phenotypes like epilepsy and sensory hypersensitivity. Through this discussion of where the current field stands, we aim to introduce perspectives moving forward in FXS research.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hyperexcitability and Homeostasis in Fragile X Syndrome

Liu

Kumar

Tsai

et al. 2022

Front. Mol. Neurosci.

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“…Typically these studies either involve pharmacological agents, which is poorly localized, or they require a considerable time between the genetic manipulation and the functional/behavioral assay, which means that the homeostatic regulatory systems have likely produced significant changes in function during the lag [45,46]. Despite this, many intriguing roles for potassium channels and their interactions with other regulatory proteins have been identified that are likely critical for normal neuronal function and may underlie neurological and psychiatric disorders [47][48][49][50][51][52]. Our results show that Opto-Kv channels are an important new tool in probing the behavioral roles of ion channels in specific neuronal populations.…”

Section: Plos Onementioning

confidence: 99%

Light-regulated voltage-gated potassium channels for acute interrogation of channel function in neurons and behavior

et al. 2021

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Voltage-gated potassium (Kv) channels regulate the membrane potential and conductance of excitable cells to control the firing rate and waveform of action potentials. Even though Kv channels have been intensely studied for over 70 year, surprisingly little is known about how specific channels expressed in various neurons and their functional properties impact neuronal network activity and behavior in vivo. Although many in vivo genetic manipulations of ion channels have been tried, interpretation of these results is complicated by powerful homeostatic plasticity mechanisms that act to maintain function following perturbations in excitability. To better understand how Kv channels shape network function and behavior, we have developed a novel optogenetic technology to acutely regulate Kv channel expression with light by fusing the light-sensitive LOV domain of Vaucheria frigida Aureochrome 1 to the N-terminus of the Kv1 subunit protein to make an Opto-Kv1 channel. Recording of Opto-Kv1 channels expressed in Xenopus oocytes, mammalian cells, and neurons show that blue light strongly induces the current expression of Opto-Kv1 channels in all systems tested. We also find that an Opto-Kv1 construct containing a dominant-negative pore mutation (Opto-Kv1(V400D)) can be used to down-regulate Kv1 currents in a blue light-dependent manner. Finally, to determine whether Opto-Kv1 channels can elicit light-dependent behavioral effect in vivo, we targeted Opto-Kv1 (V400D) expression to Kv1.3-expressing mitral cells of the olfactory bulb in mice. Exposure of the bulb to blue light for 2–3 hours produced a significant increase in sensitivity to novel odors after initial habituation to a similar odor, comparable to behavioral changes seen in Kv1.3 knockout animals. In summary, we have developed novel photoactivatable Kv channels that provide new ways to interrogate neural circuits in vivo and to examine the roles of normal and disease-causing mutant Kv channels in brain function and behavior.

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“…Cterminus domain mutations such as R534H and G482S have been predicted to alter RNA binding and recognition (29). In addition, the frame shift mutation (G538fs* 23) in the open reading frame of FMRP has been shown to introduce novel sequences, which drastically alter the cellular localization of FMRP (30). These mutational studies emphasize the probable structural defects and the contribution of individual domains of FMRP.…”

Section: Introductionmentioning

confidence: 99%

“…Only a few studies address the mechanism of these interactions through truncations and mutations of FMRP. The N-terminus domain of FMRP is shown to modulate the expression and activity of several ion channels (22,23) while the RGG domain in the C-terminus is implicated in RNA binding and consequent gene expression (24,25). Further, the I304N mutation of FMRP, which results in a severe form of FXS, illustrates the importance of KH domains in polysome association and translation regulation (16,26).…”

Section: Introductionmentioning

confidence: 99%

Function of FMRP domains in regulating distinct roles of neuronal protein synthesis

D’Souza

Ramakrishna

Radhakrishna

et al. 2021

Preprint

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The Fragile X Mental Retardation Protein (FMRP) is an RNA Binding Protein that regulates translation of mRNAs, essential for synaptic development and plasticity. FMRP interacts with a specific set of mRNAs and aids in their microtubule dependent transport and regulates their translation through its association with ribosomes. However, the biochemical role of individual domains of FMRP in forming neuronal granules and associating with microtubules and ribosomes is currently undefined. Here, we report that the C-terminus domain of FMRP is sufficient to bind to ribosomes as well as polysomes akin to the full-length protein. Furthermore, the C-terminus domain alone is essential and responsible for FMRP-mediated translation repression in neurons. However, FMRP-mediated puncta formation and microtubule association is favored by the synergistic combination of FMRP domains and not by individual domains. Interestingly, we show that the phosphorylation of hFMRP at Serine-500 is important in modulating the dynamics of translation by controlling ribosome/polysome association. This is a fundamental mechanism governing the size and number of FMRP puncta, which appear to contain actively translating ribosomes. Finally through the use of pathogenic mutations, we emphasize the hierarchy of the domains of FMRP in their contribution to translation regulation.

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FMRP(1–297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome

Cited by 24 publications

References 56 publications

Hyperexcitability and Homeostasis in Fragile X Syndrome

Hyperexcitability and Homeostasis in Fragile X Syndrome

Light-regulated voltage-gated potassium channels for acute interrogation of channel function in neurons and behavior

Function of FMRP domains in regulating distinct roles of neuronal protein synthesis

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