FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

Bonnycastle, Katherine; Kind, Peter C.; Cousin, Michael A.

doi:10.1101/2020.09.10.291062

Cited by 3 publications

(3 citation statements)

References 59 publications

(136 reference statements)

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“…4e-k). Recently, it was reported that the FMRP-R138Q mutant fails to restore activity-dependent bulk endocytosis (ADBE) in Fmr1-KO neurons, perhaps through the loss of BK channel interaction 32 . Our EM measurements also revealed a significant increase in the density of presynaptic vesicles in Fmr1 R138Q hippocampal termini (Fig.…”

Section: Discussionmentioning

confidence: 99%

Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

et al. 2021

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Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.

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Section: Discussionmentioning

confidence: 99%

Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

et al. 2021

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“…Fmr1 KO neurons also display alterations in the size of functional SV pools (Deng et al, 2011;Klemmer et al, 2011;Bonnycastle et al 2020). This may reflect compensation for reduced activity-dependent bulk endocytosis (Bonnycastle et al 2020), a mode of endocytosis only triggered during periods of elevated neuronal activity (Kokotos & Cousin, 2015). However, altered SV pool sizes are unlikely to contribute to spontaneous SV fusion, since no increase in action potential-driven SV fusion was observed in Fmr1 KO neurons, in agreement with (Bonnycastle et al 2020).…”

Section: Increased Spontaneous Sv Fusion In Fmr1 Ko Neurons Depends On Spontaneous Activitymentioning

confidence: 88%

“…It also regulates both the density and localization of N-type calcium channels (Ca V 2.2) in dorsal root ganglion (DRG) cells (Ferron et al, 2014(Ferron et al, , 2020. Fmr1 KO neurons also display alterations in the size of functional SV pools (Deng et al, 2011;Klemmer et al, 2011;Bonnycastle et al 2020). This may reflect compensation for reduced activity-dependent bulk endocytosis (Bonnycastle et al 2020), a mode of endocytosis only triggered during periods of elevated neuronal activity (Kokotos & Cousin, 2015).…”

Section: Increased Spontaneous Sv Fusion In Fmr1 Ko Neurons Depends On Spontaneous Activitymentioning

confidence: 99%

Reciprocal regulation of spontaneous synaptic vesicle fusion by Fragile X mental retardation protein and group I metabotropic glutamate receptors

Subrahmanyam

Dwivedi

Rashid

et al. 2021

Journal of Neurochemistry

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Fragile X mental retardation protein (FMRP) is a neuronal protein mediating multiple functions, with its absence resulting in one of the most common monogenic causes of autism, Fragile X syndrome (FXS). Analyses of FXS pathophysiology have identified a range of aberrations in synaptic signaling pathways and plasticity associated with group I metabotropic glutamate (mGlu) receptors. These studies, however, have mostly focused on the post-synaptic functions of FMRP and mGlu receptor activation, and relatively little is known about their presynaptic effects. Neurotransmitter release is mediated via multiple forms of synaptic vesicle (SV) fusion, each of which contributes to specific neuronal functions. The impacts of mGlu receptor activation and loss of FMRP on these SV fusion events remain unexplored. Here we combined electrophysiological and fluorescence imaging analyses on primary hippocampal cultures prepared from an Fmr1 knockout (KO) rat model. Compared to wild-type (WT) | 1095 SUBRAHMANYAM et Al.

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Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missenseFmr1mutant mouse model of Fragile X syndrome

Prieto

Folci

Poupon

et al. 2020

Preprint

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Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the bestdescribed monogenic cause of autism. FXS is usually caused by a CGG-repeat expansion in the FMR1 gene leading to its silencing and the loss-of-expression of the Fragile X Mental Retardation Protein (FMRP). Missense mutations were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS in these patients, we generated a knock-in mouse model (Fmr1 R138Q ) expressing the FMRP-R138Q protein. We demonstrate that the Fmr1 R138Q hippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, highresolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits in Fmr1 R138Q mice.These findings reveal that the R138Q mutation impacts the postsynaptic function of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients. IntroductionThe formation of functional synapses in the developing brain is fundamental to establishing efficient neuronal communication and plasticity, which underlie cognitive processes. In the past years, synaptic dysfunction has clearly emerged as a critical factor in the aetiology of neurodevelopmental disorders including Autism Spectrum disorder (ASD) and Intellectual Disability (ID). X-linked ID (XLID) accounts for 5-10% of ID patients and is caused by mutations in genes located on the X chromosome.The Fragile X Syndrome (FXS) is the most frequent form of inherited XLID and the first monogenic cause of ASD with a prevalence of 1:4000 males and 1:7000 females 1 . The majority of FXS patients exhibit mild-to-severe ID associated with significant learning and memory impairments, Attention Deficit Hyperactivity Disorder (ADHD) and autistic-like features 2-4 . To date, no effective therapeutic strategies are available.FXS generally results from a massive expansion of the trinucleotide CGG (>200 repeats) in the 5'-UTR region of the FMR1 gene leading to its transcriptional silencing and consequently, the lack of expression of the encoded Fragile X Mental Retardation Protein (FMRP) 2,5 . FMRP is an RNA-binding protein that binds a large subset of mRNAs in the mammalian brain and is a key component of RNA granules. These granules transport translationally-repressed mRNAs essential for the synaptic function along axons and dendrites 1,3 . Neuronal activation triggers the local translation of these critical mRNAs at synapses allowing spine maturation and elimination, which are essential processes to shape a functional neuronal network in the developing brain. Accordingly, the lack of FMRP expression in FXS patients and Fmr1 knockout (Fmr1-KO) animal models leads to a pathological increase in immature dendritic protrusions due to a failure in the synapse maturation and/or elimination processes 6 . These defects co...

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FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

Cited by 3 publications

References 59 publications

Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

Reciprocal regulation of spontaneous synaptic vesicle fusion by Fragile X mental retardation protein and group I metabotropic glutamate receptors

Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missenseFmr1mutant mouse model of Fragile X syndrome

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