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 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.

Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome

2011 ◽  
Vol 217 (1) ◽  
pp. 143-151 ◽  
Author(s):  
Surabi Veeraragavan ◽  
Nghiem Bui ◽  
Jennie R. Perkins ◽  
Lisa A. Yuva-Paylor ◽  
Randall L. Carpenter ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Behavioral Phenotypes

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 Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

2019 ◽  
Vol 13 ◽  
Author(s):  
Chloé Felgerolle ◽  
Betty Hébert ◽  
Maryvonne Ardourel ◽  
Géraldine Meyer-Dilhet ◽  
Arnaud Menuet ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Visual Behavior

scholarly journals Beneficial effects of sound exposure on auditory cortex development in a mouse model of Fragile X Syndrome

2020 ◽  
Vol 134 ◽  
pp. 104622 ◽  
Author(s):  
Anna O. Kulinich ◽  
Sarah M. Reinhard ◽  
Maham Rais ◽  
Jonathan W. Lovelace ◽  
Veronica Scott ◽  
...  
Keyword(s):  
Mouse Model ◽  
Auditory Cortex ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Beneficial Effects ◽  
Sound Exposure

scholarly journals Baclofen-Associated Neurophysiologic Target Engagement Across Species in Fragile X Syndrome

2021 ◽  
Author(s):  
Carrie R. Jonak ◽  
Ernest V. Pedapati ◽  
Lauren M. Schmitt ◽  
Samantha A. Assad ◽  
Manbir S. Sandhu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Gamma Activity ◽  
Multielectrode Array ◽  
Target Engagement ◽  
Human Experiments ◽  
Gamma Power ◽  
Delayed Language Development

Abstract Background: Fragile X Syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. Methods: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC). Results: In Fmr1 KO mice and in humans with FXS, baclofen use was synchronously associated with suppression of elevated gamma power and increase in theta power at rest. In the Frm1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. Conclusions: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. Trial Registration: The human experiments are registered under NCT02998151.

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.

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