scholarly journals Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome

2020 ◽  
Vol 123 (6) ◽  
pp. 2101-2121 ◽  
Author(s):  
Anna O. Nguyen ◽  
Devin K. Binder ◽  
Iryna M. Ethell ◽  
Khaleel A. Razak
Keyword(s):  
Mouse Model ◽  
Inferior Colliculus ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Abnormal Development ◽  
Sensory Sensitivity ◽  
Auditory Responses ◽  
Underlying Mechanisms ◽  
Early Developmental

Autism spectrum disorders (ASD) are commonly associated with sensory sensitivity issues, but the underlying mechanisms are unclear. This study presents novel evidence for neural correlates of auditory hypersensitivity in the developing inferior colliculus (IC) in the Fmr1 knockout (KO) mouse, a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of ASD. Responses begin to show genotype differences between postnatal days 14 and 21, suggesting an early developmental treatment window.

scholarly journals Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome

2021 ◽  
Author(s):  
Chaojuan Yang ◽  
Yonglu Tian ◽  
Feng Su ◽  
Yangzhen Wang ◽  
Mengna Liu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Visual Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Local Network ◽  
V1 Neurons ◽  
Processing Deficits

AbstractMany people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

Seizing control of fragile X syndrome

2020 ◽  
Vol 12 (524) ◽  
pp. eaba2902
Author(s):  
Emily K. Osterweil
Keyword(s):  
Mouse Model ◽  
Inferior Colliculus ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Audiogenic Seizures ◽  
Glutamatergic Neurons

Loss of Fmr1 in glutamatergic neurons of the inferior colliculus is responsible for audiogenic seizures in the fragile X syndrome mouse model.

scholarly journals Attention Bias and Prodromal Anxiety Symptoms in Toddlers With Fragile X Syndrome and Down Syndrome

2021 ◽  
Vol 126 (2) ◽  
pp. 167-181
Author(s):  
Kayla Smith ◽  
Abigail L. Hogan ◽  
Elizabeth Will ◽  
Jane E. Roberts
Keyword(s):  
Down Syndrome ◽  
Fragile X Syndrome ◽  
Symptom Severity ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Autism Spectrum ◽  
Behavioral Risk ◽  
Typically Developing ◽  
Attentional Avoidance ◽  
Underlying Mechanisms

Abstract Early identification of behavioral risk markers for anxiety is essential to optimize long-term outcomes in children with neurodevelopmental disorders. This study analyzed attentional avoidance and its relation to anxiety and autism spectrum disorder (ASD) symptomatology during social and nonsocial fear conditions in toddlers with fragile X syndrome (FXS) and Down syndrome (DS). Toddlers with FXS and DS exhibited increased nonsocial attentional avoidance relative to typically developing (TD) toddlers. Attentional avoidance was not related to anxiety symptom severity in any group; however, higher ASD symptom severity was related to more social attentional avoidance in the FXS and TD groups. Findings suggest that there may be different underlying mechanisms driving attentional avoidance across neurodevelopmental disorders.

scholarly journals Impaired hippocampal representation of place in the Fmr1-knockout mouse model of Fragile X syndrome

2017 ◽  
Author(s):  
Tara Arbab ◽  
Cyriel MA Pennartz ◽  
Francesco P Battaglia
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Hippocampal Neurons ◽  
Spatial Information ◽  
Fragile X ◽  
Memory Function ◽  
Autism Spectrum ◽  
Spatial Representations ◽  
Potential Biomarker

AbstractFragile X syndrome (FXS) is an X-chromosome linked intellectual disability and the most common genetic cause of autism spectrum disorder (ASD). Building upon demonstrated deficits in neuronal plasticity and spatial memory in FXS, we investigated how spatial information processing is affected in vivo in an FXS mouse model (Fmr1-KO). Healthy hippocampal neurons (so-called place cells) exhibit place-related activity during spatial exploration, and the stability of these spatial representations can be taken as an index of memory function. We find impaired stability and reduced specificity of Fmr1-KO spatial representations. This is a potential biomarker for the cognitive dysfunction observed in FXS, informative on the ability to integrate sensory information into an abstract representation and successfully retain this conceptual memory. Our results provide key insight into the biological mechanisms underlying cognitive disabilities in FXS and ASD, paving the way for a targeted approach to remedy these.

Abnormal neurogensis in the hippocampus of a mouse model of fragile X syndromes

2007 ◽  
Vol 30 (4) ◽  
pp. 80
Author(s):  
B Eadie ◽  
B Christie
Keyword(s):  
Mouse Model ◽  
Learning And Memory ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Fmr1 Gene ◽  
Learning Impairment

Fragile X syndrome is the most common inherited form of mental retardation. It is a neurodevelopmental disorder that is similar in clinical presentation to autism spectrum disorder. However, unlike autism, Fragile X syndrome is caused by the silencing of a single gene, and in recent years, a mouse model of Fragile X syndrome has been generated by deletion of the Fmr1 gene. Surprisingly, a clear neurobiological basis for the learning impairment observed in both these knockout mice and patients has been difficult to elucidate. We hypothesized that neurogenesis, a process that continues into adulthood in the hippocampus, may be abnormal in this syndrome. Support for such a hypothesis comes from the findings that these new neurons may disproportionately contribute to synaptic plasticity in networks engaged during learning and memory. We have shown that the survival of new cells in the hippocampus of young Fmr1 knockout mice is significantly decreased in the ventral hippocampus, a sub-region which may be more involved with emotional, rather than, spatial memory. Further experiments are being conducted to assess the differentiation of these new cells into neurons and glia. We are also characterizing the normal expression of the Fmr1 gene product, FMRP, across the phases of neurogenesis in control mice. In conclusion, we have discovered a clear impairment in a process that may be critical to emotionally-significant learning and memory in a mouse model of Fragile X syndrome.

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

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sam A. Booker ◽  
Aleksander P. F. Domanski ◽  
Owen R. Dando ◽  
Adam D. Jackson ◽  
John T. R. Isaac ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Dendritic Spine ◽  
Fragile X ◽  
Super Resolution ◽  
Fold Increase ◽  
Autism Spectrum ◽  
Spine Morphology ◽  
Single Spine ◽  
Spine Function

Abstract Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, fewer spines are required to trigger an action potential with near-simultaneous uncaging at multiple spines. This is, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents, and increased NMDA receptor signaling. Using super-resolution microscopy we detect no change in dendritic spine morphology, indicating no structure-function relationship at this age. However, ultrastructural analysis shows a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine glutamate currents. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.

scholarly journals The mouse model of fragile X syndrome exhibits deficits in contagious itch behavior

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Rodrigo Gonzales-Rojas ◽  
Amtul-Noor Rana ◽  
Peter Mason ◽  
Christopher Renfro ◽  
Vallabhi Annaluru ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Assessment Tool ◽  
Fragile X ◽  
Autism Spectrum ◽  
Assessment Tools ◽  
Learning Ability ◽  
Typically Developing ◽  
Spectrum Disorders

Abstract Individuals with autism spectrum disorders (ASDs) imitate observed behavior less than age-matched and typically developing peers, resulting in deterred learning ability and social interaction. However, this deficit lacks preclinical assessment tools. A previous study has shown that mice exhibit contagious itch behavior while viewing a scratching demonstrator mouse, as opposed to an ambulating demonstrator mouse, but whether autism mouse models imitate observed scratching behavior remains unknown. Here, we investigated contagious itch behavior in the mouse model of fragile X syndrome (FXS), a common form of inherited intellectual disabilities with a high risk for ASDs. We found that the mouse model of FXS shows deficits in contagious itch behavior. Our findings can be used as a new preclinical assessment tool for measuring imitative deficits in the study of neurodevelopmental disorders including FXS.

scholarly journals Deletion of Fmr1 from Forebrain Excitatory Neurons Triggers Abnormal Cellular, EEG, and Behavioral Phenotypes in the Auditory Cortex of a Mouse Model of Fragile X Syndrome

2019 ◽  
Vol 30 (3) ◽  
pp. 969-988 ◽  
Author(s):  
Jonathan W Lovelace ◽  
Maham Rais ◽  
Arnold R Palacios ◽  
Xinghao S Shuai ◽  
Steven Bishay ◽  
...  
Keyword(s):  
Mouse Model ◽  
Auditory Cortex ◽  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Behavioral Phenotypes ◽  
Excitatory Neurons ◽  
Gamma Power ◽  
Processing Deficits

Abstract Fragile X syndrome (FXS) is a leading genetic cause of autism with symptoms that include sensory processing deficits. In both humans with FXS and a mouse model [Fmr1 knockout (KO) mouse], electroencephalographic (EEG) recordings show enhanced resting state gamma power and reduced sound-evoked gamma synchrony. We previously showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to these phenotypes by affecting perineuronal nets (PNNs) around parvalbumin (PV) interneurons in the auditory cortex of Fmr1 KO mice. However, how different cell types within local cortical circuits contribute to these deficits is not known. Here, we examined whether Fmr1 deletion in forebrain excitatory neurons affects neural oscillations, MMP-9 activity, and PV/PNN expression in the auditory cortex. We found that cortical MMP-9 gelatinase activity, mTOR/Akt phosphorylation, and resting EEG gamma power were enhanced in CreNex1/Fmr1Flox/y conditional KO (cKO) mice, whereas the density of PV/PNN cells was reduced. The CreNex1/Fmr1Flox/y cKO mice also show increased locomotor activity, but not the anxiety-like behaviors. These results indicate that fragile X mental retardation protein changes in excitatory neurons in the cortex are sufficient to elicit cellular, electrophysiological, and behavioral phenotypes in Fmr1 KO mice. More broadly, these results indicate that local cortical circuit abnormalities contribute to sensory processing deficits in autism spectrum disorders.

scholarly journals Altered dendritic spine function and integration in a mouse model of Fragile X Syndrome

2018 ◽  
Author(s):  
Sam A. Booker ◽  
Aleksander P.F. Domanski ◽  
Owen R. Dando ◽  
Adam D. Jackson ◽  
John T.R. Isaac ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Dendritic Spine ◽  
Fragile X ◽  
Super Resolution ◽  
Fold Increase ◽  
Autism Spectrum ◽  
Spine Morphology ◽  
Single Spine ◽  
Spine Function

AbstractCellular and circuit hyperexcitability are core features of Fragile X Syndrome and related autism spectrum disorder models. However, a synaptic basis for this hyperexcitability has proved elusive. We show in a mouse model of Fragile X Syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, near-simultaneous uncaging at multiple spines revealed fewer spines are required to trigger an action potential. This arose, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents. Super-resolution microscopy revealed no change in dendritic spine morphology, pointing to an absence of a structure-function relationship. However, ultrastructural analysis revealed a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine excitatory currents following glutamate uncaging. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.

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