Altered dendritic spine function and integration in a mouse model of fragile X syndrome

Booker, Sam A.; Domanski, Aleksander Peter Frederick; Dando, Owen; Jackson, Adam D.; Isaac, John T.R.; Hardingham, Giles E.; Wyllie, David J. A.; Kind, Peter C.

doi:10.1038/s41467-019-11891-6

Cited by 51 publications

(44 citation statements)

References 55 publications

(79 reference statements)

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“…Reduced orientation tuning of the neurons in the visual cortex correlated with the decreased ability to resolve different orientations of sinusoidal grating stimuli in both mice and human individuals with FX (Goel et al, 2018 ). Furthermore, altered dendritic spine function and integration were found in layer 4 of the somatosensory cortex in FX mice (Booker et al, 2019 ). Structural and functional imaging studies of FX mice revealed local hyperconnectivity and long-range hypoconnectivity in V1 (Haberl et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Impaired Adaptation and Laminar Processing of the Oddball Paradigm in the Primary Visual Cortex of Fmr1 KO Mouse

Pak

Kissinger

Chubykin

2021

Front. Cell. Neurosci.

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Both adaptation and novelty detection are an integral part of sensory processing. Recent animal oddball studies have advanced our understanding of circuitry underlying contextual processing in early sensory areas. However, it is unclear how adaptation and mismatch (MM) responses depend on the tuning properties of neurons and their laminar position. Furthermore, given that reduced habituation and sensory overload are among the hallmarks of altered sensory perception in autism, we investigated how oddball processing might be altered in a mouse model of fragile X syndrome (FX). Using silicon probe recordings and a novel spatial frequency (SF) oddball paradigm, we discovered that FX mice show reduced adaptation and enhanced MM responses compared to control animals. Specifically, we found that adaptation is primarily restricted to neurons with preferred oddball SF in FX compared to WT mice. Mismatch responses, on the other hand, are enriched in the superficial layers of WT animals but are present throughout lamina in FX animals. Last, we observed altered neural dynamics in FX mice in response to stimulus omissions. Taken together, we demonstrated that reduced feature adaptation coexists with impaired laminar processing of oddball responses, which might contribute to altered sensory perception in FX syndrome and autism.

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Section: Introductionmentioning

confidence: 99%

Impaired Adaptation and Laminar Processing of the Oddball Paradigm in the Primary Visual Cortex of Fmr1 KO Mouse

Pak

Kissinger

Chubykin

2021

Front. Cell. Neurosci.

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“…It is likely that the observed reduction in ADBE reflects a compensatory or homeostatic mechanism to counteract the increased excitability in FXS and Fmr1 KO models (Booker et al, 2019; Das Sharma et al, 2020; Zhang et al, 2014). BK channel openers decrease hyperexcitability in Fmr1 KO models both in vitro and in vivo by increasing hyperpolarization, resulting in decreased calcium influx in nerve terminals.…”

Section: Resultsmentioning

confidence: 99%

“…A homeostatic reduction in ADBE in response to increased hyperexcitability would not be a homogenous adaptation across the brain, since neurons that display high firing rates would be disproportionately impacted. Therefore, even if reduced ADBE is not a causal mechanism in FXS, it may still be a valuable therapeutic intervention point to correct hyperexcitability in specific circuits (Booker et al, 2019; Das Sharma et al, 2020). Future studies are now required to determine whether modulation of ADBE can sculpt circuit activity in FXS (and other autism models that display hyperexcitability - such as SynGAP haploinsufficiency disorder (Gamache et al, 2020)).…”

Section: Resultsmentioning

confidence: 99%

“…Hyperexcitability of neuronal circuits is a key feature of fragile X syndrome (FXS) (Booker et al, 2019; Das Sharma et al, 2020), one of the most common monogenic causes of intellectual disability (ID) and autism spectrum disorder (Mefford et al, 2012). Most FXS cases are caused by a CGG trinucleotide expansion in the 5’ untranslated region of the FMR1 gene which encodes FMRP, leading to hypermethylation of the promoter and silencing of the FMR1 gene.…”

Section: Introductionmentioning

confidence: 99%

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

Bonnycastle

Kind

Cousin

2020

Preprint

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Synaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. FMRP is an established translation repressor, however it also has translation-independent presynaptic roles, including regulation of the trafficking and function of specific ion channels. Since defects in SV recycling are exacerbated during intense neuronal activity, we investigated whether these events were disproportionately affected by the absence of FMRP. We revealed that primary neuronal cultures from a Fmr1 knockout rat model display a specific defect in activity-dependent bulk endocytosis (ADBE). ADBE is dominant during intense neuronal activity, and this defect resulted in an inability of Fmr1 knockout neurons to sustain SV recycling during trains of high frequency stimulation. Using a molecular replacement strategy, we revealed that a human FMRP interaction mutant failed to correct ADBE dysfunction in knockout neurons. Therefore, FMRP performs a key role in sustaining neurotransmitter release via selective control of the endocytosis mode, ADBE.SIGNIFICANCE STATEMENTLoss of fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), however whether its loss has a direct role in neurotransmitter release remains a matter of debate. We demonstrate that neurons lacking FMRP display a specific defect in a mechanism that sustains neurotransmitter release during intense neuronal firing, called activity-dependent bulk endocytosis (ADBE). This discovery provides key insights into mechanisms of brain communication that occur due to loss of FMRP function. Importantly it also reveals ADBE as a potential therapeutic target to correct the circuit hyperexcitabilty observed in FXS.

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“…These findings suggest that MIS generation is an efficient mechanism to increase connectivity and/or strengthen connections on existing synapses during learning. Furthermore, in neurological disorders characterized by increased cortical connectivity and disrupted network function such as Fragile X syndrome (Bureau et al, 2008;Zhang et al, 2014), the number of MIS are also significantly increased (Booker et al, 2019). This structural plasticity mechanism could be driven by differences in cortical network activity.…”

Section: Discussionmentioning

confidence: 99%

Wnt Signaling Through Nitric Oxide Synthase Promotes the Formation of Multi-Innervated Spines

McLeod

Boyle

Marzo

et al. 2020

Front. Synaptic Neurosci.

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Structural plasticity of synapses correlates with changes in synaptic strength. Dynamic modifications in dendritic spine number and size are crucial for long-term potentiation (LTP), the cellular correlate of learning and memory. Recent studies have suggested the generation of multi-innervated spines (MIS), in the form of several excitatory presynaptic inputs onto one spine, are crucial for hippocampal memory storage. However, little is known about the molecular mechanisms underlying MIS formation and their contribution to LTP. Using 3D enhanced resolution confocal images, we examined the contribution of Wnt synaptic modulators in MIS formation in the context of LTP. We show that blockage of endogenous Wnts with specific Wnt antagonists supresses the formation of MIS upon chemical LTP induction in cultured hippocampal neurons. Gain-and lossof-function studies demonstrate that Wnt7a signaling promotes MIS formation through the postsynaptic Wnt scaffold protein Disheveled 1 (Dvl1) by stimulating neuronal nitric oxide (NO) synthase (nNOS). Subsequently, NO activates soluble guanylyl cyclase (sGC) to increase MIS formation. Consistently, we observed an enhanced frequency and amplitude of excitatory postsynaptic currents. Collectively, our findings identify a unique role for Wnt secreted proteins through nNOS/NO/sGC signaling to modulate MIS formation during LTP.

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Altered dendritic spine function and integration in a mouse model of fragile X syndrome

Cited by 51 publications

References 55 publications

Impaired Adaptation and Laminar Processing of the Oddball Paradigm in the Primary Visual Cortex of Fmr1 KO Mouse

Impaired Adaptation and Laminar Processing of the Oddball Paradigm in the Primary Visual Cortex of Fmr1 KO Mouse

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

Wnt Signaling Through Nitric Oxide Synthase Promotes the Formation of Multi-Innervated Spines

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