Structural and Functional Abnormalities in the Olfactory System of Fragile X Syndrome Models

Bodaleo, Felipe; Tapia-Monsalves, Carola; Rio, Christian A. Cea-Del; González-Billault, Christian; Nunez-Parra, Alexia

doi:10.3389/fnmol.2019.00135

Cited by 16 publications

(8 citation statements)

References 117 publications

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“…To begin with, three regions that are involved in olfaction, the piriform cortex, olfactory bulb, and anterior commissure were altered in Fmr1-Δ exon 8 rats. Olfaction has not been well characterized in FXS, but it is impaired in rodent models of FXS 36 . Individuals with FXS can also be hypersensitive to auditory and visual stimuli.…”

Section: Discussionmentioning

confidence: 99%

Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1

et al. 2020

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Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by mutations in the FMR1 gene. Neuroanatomical alterations have been reported in both male and female individuals with FXS, yet the morphological underpinnings of these alterations have not been elucidated. In the current study, we found structural changes in both male and female rats that model FXS, some of which are similarly impaired in both sexes, including the superior colliculus and periaqueductal gray, and others that show sex-specific changes. The splenium of the corpus callosum, for example, was only impaired in males. We also found reduced axonal caliber in the splenium, offering a mechanism for its structural changes. Furthermore, we found that overall, male rats have higher brain-wide diffusion than female rats. Our results provide insight into which brain regions are vulnerable to a loss of Fmr1 expression and reveal an impairment at the level of the axon that could cause structural changes in white matter regions.

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Section: Discussionmentioning

confidence: 99%

Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1

et al. 2020

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“…Loss of FMRP-mediated regulation of BK channel conductance (Deng et al, 2013 ; Deng and Klyachko, 2016b ) could therefore conceivably account for impaired habituation in FMR1 KO animals, although this has not been directly tested yet. While less characterized, there is evidence for altered olfaction in FXS models as well (Bodaleo et al, 2019 ). Interestingly, studies in FMR1 KO mice (Schilit Nitenson et al, 2015 ) and a FXS drosophila model (Franco et al, 2017 ) both found that FXS animals exhibited decreased odor sensitivity, contrary to findings from other sensory domains.…”

Section: Behavioral Consequences Of Hyperexcitable Circuits In Fxsmentioning

confidence: 99%

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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“…Our findings of significantly lower [ 18 F]FPEB binding potential (BP ND ) in these areas provide support for the role of mGluR5 in the neurobiology of FXS. Anxiety is frequently reported in this population, which may explain the significant group differences we observed in the insula and olfactory cortex 19 , 23 . Evidence in support of these findings also comes from preclinical studies of the Fmr1 KO mouse using the Morris water maze task and the mirrored chamber test 24 – 26 .…”

Section: Discussionmentioning

confidence: 62%

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker

Mody

Petibon

Han

et al. 2021

Sci Rep

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Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the Fragile X Mental Retardation (FMR1) gene. The resulting loss of Fragile X Mental Retardation Protein (FMRP) leads to excessive glutamate signaling via metabotropic glutamate subtype 5 receptors (mGluR5) which has been implicated in the pathogenesis of the disorder. In the present study we used the radioligand 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB) in simultaneous PET-MR imaging of males with FXS and age- and gender-matched controls to assess the availability of mGlu5 receptors in relevant brain areas. Patients with FXS showed lower [18F]FPEB binding potential (p < 0.01), reflecting reduced mGluR5 availability, than the healthy controls throughout the brain, with significant group differences in insula, anterior cingulate, parahippocampal, inferior temporal and olfactory cortices, regions associated with deficits in inhibition, memory, and visuospatial processes characteristic of the disorder. The results are among the first to provide in vivo evidence of decreased availability of mGluR5 in the brain in individuals with FXS than in healthy controls. The consistent results across the subjects, despite the tremendous challenges with neuroimaging this population, highlight the robustness of the protocol and support for its use in drug occupancy studies; extending our radiotracer development and application efforts from mice to humans.

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Structural and Functional Abnormalities in the Olfactory System of Fragile X Syndrome Models

Cited by 16 publications

References 117 publications

Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1

Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1

Hyperexcitability and Homeostasis in Fragile X Syndrome

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker

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