Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

Ethridge, Lauren E.; White, Steven J.; Mosconi, Matthew W.; Wang, Jun; Pedapati, Ernest V.; Erickson, Craig A.; Byerly, Matthew J.; Sweeney, John A.

doi:10.1186/s13229-017-0140-1

Cited by 122 publications

(206 citation statements)

References 56 publications

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“…Increased activation of left hemispheric circuitry, including superior temporal gyrus, was observed in FXS subjects during an auditory temporal discrimination task . FXS subjects also show reduced synchronization of neural responses to time‐varying signals, suggesting impairments in temporal processing . Rojas et al showed that tone‐evoked responses measured using magnetic fields are higher in the auditory cortex of individuals with FXS .…”

Section: Fmrp Loss Alters Auditory Cortical Activitymentioning

confidence: 99%

“…46 FXS subjects also show reduced synchronization of neural responses to time-varying signals, suggesting impairments in temporal processing. 109 Rojas et al 110 showed that tone-evoked responses measured using magnetic fields are higher in the auditory cortex of individuals with FXS. 110 EEG recordings revealed increased gamma frequency band power in resting state EEG of FXS patients.…”

Section: Auditory Cortical Activit Ymentioning

confidence: 99%

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Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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Autism spectrum disorders (ASD) are strongly associated with auditory hypersensitivity or hyperacusis (difficulty tolerating sounds). Fragile X syndrome (FXS), the most common monogenetic cause of ASD, has emerged as a powerful gateway for exploring underlying mechanisms of hyperacusis and auditory dysfunction in ASD. This review discusses examples of disruption of the auditory pathways in FXS at molecular, synaptic, and circuit levels in animal models as well as in FXS individuals. These examples highlight the involvement of multiple mechanisms, from aberrant synaptic development and ion channel deregulation of auditory brainstem circuits, to impaired neuronal plasticity and network hyperexcitability in the auditory cortex. Though a relatively new area of research, recent discoveries have increased interest in auditory dysfunction and mechanisms underlying hyperacusis in this disorder. This rapidly growing body of data has yielded novel research directions addressing critical questions regarding the timing and possible outcomes of human therapies for auditory dysfunction in ASD.

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Section: Fmrp Loss Alters Auditory Cortical Activitymentioning

confidence: 99%

Section: Auditory Cortical Activit Ymentioning

confidence: 99%

Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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“…Differences in synaptic activity are a defining and unifying characteristic of animal models of autism—virtually, every report of an autism model includes electrophysiological characterization showing altered synaptic transmission. The directionality of change in synaptic activity is also variable between models; for example Ube3a 2xTG mice show reduced cortical excitability [ 32 ] while Fragile X [ 53 , 54 ] mice show increased. Viewed through this activity-dependent lens, the bidirectionality of our data makes more sense.…”

Section: Discussionmentioning

confidence: 99%

Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models

et al. 2018

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BackgroundAutism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors. Mouse models of specific risk factors have been successful in identifying molecular mechanisms associated with a given factor. However, comparisons among different models to elucidate underlying common pathways or to define clusters of biologically relevant disease subtypes have been complicated by different methodological approaches or different brain regions examined by the labs that developed each model. Here, we use a novel proteomic technique, quantitative multiplex co-immunoprecipitation or QMI, to make a series of identical measurements of a synaptic protein interaction network in seven different animal models. We aim to identify molecular disruptions that are common to multiple models.MethodsQMI was performed on 92 hippocampal and cortical samples taken from seven mouse models of ASD: Shank3B, Shank3Δex4-9, Ube3a2xTG, TSC2, FMR1, and CNTNAP2 mutants, as well as E12.5 VPA (maternal valproic acid injection on day 12.5 post-conception). The QMI panel targeted a network of 16 interacting, ASD-linked, synaptic proteins, probing 240 potential co-associations. A custom non-parametric statistical test was used to call significant differences between ASD models and littermate controls, and Hierarchical Clustering by Principal Components was used to cluster the models using mean log2 fold change values.ResultsEach model displayed a unique set of disrupted interactions, but some interactions were disrupted in multiple models. These tended to be interactions that are known to change with synaptic activity. Clustering revealed potential relationships among models and suggested deficits in AKT signaling in Ube3a2xTG mice, which were confirmed by phospho-western blots.ConclusionsThese data highlight the great heterogeneity among models, but suggest that high-dimensional measures of a synaptic protein network may allow differentiation of subtypes of ASD with shared molecular pathology.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0229-1) contains supplementary material, which is available to authorized users.

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“…For example, about one-third of FXS-affected individuals exhibit cortical hyperexcitability. 336 If such hyperexcitability can be modeled in FXS iPSC-differentiated neurons, it will provide an excellent platform for understanding the molecular mechanism of the presence and absence of hyperexcitability and provide an opportunity to prescreen individuals for clinical trials. Therefore, hPSCs are essential for validating the molecular, cellular, and functional FXS deficits that we have known for years on the basis of animal studies.…”

Section: Human Stem Cells For Modeling Neurodevelopmental Disordersmentioning

confidence: 99%

“…For example, recent work has indicated that variability in behavior and cognition in FXS could be linked to variability in electrical activity in the brain of FXSaffected individuals, as measured by EEG. 223,336 One solution is the establishment of high-quality iPSCs from individuals with well-characterized and stratified clinical features. Stratification of affected individuals and cells could enable more effective linkage of disease characteristics with cellular phenotypes and better design of clinical trials.…”

Section: Challenges and Perspectives Clinical Variabilitymentioning

confidence: 99%

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

Zhao

Bhattacharyya

2018

The American Journal of Human Genetics

129

103

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The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals. Human pluripotent stem cells have emerged as a much-needed model system for investigating human-specific biology and disease mechanisms. However, questions remain regarding whether these cell-culture-based models are sufficient or even necessary. In this review, we summarize human-specific features of neurodevelopment and the most common neurodevelopmental disorders, present discrepancies between animal models and human diseases, demonstrate how human stem cell models can provide meaningful information, and discuss the challenges that exist in our pursuit to understand distinctively human aspects of neurodevelopment and brain disease. This information argues for a more thoughtful approach to disease modeling through consideration of the valuable features and limitations of each model system, be they human or animal, to mimic disease characteristics.

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Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

Cited by 122 publications

References 56 publications

Mechanisms underlying auditory processing deficits in Fragile X syndrome

Mechanisms underlying auditory processing deficits in Fragile X syndrome

Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

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