scholarly journals Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Julia Berzhanskaya ◽  
Marnie A. Phillips ◽  
Jing Shen ◽  
Matthew T. Colonnese
Keyword(s):  
Fragile X Syndrome ◽  
Rat Model ◽  
Fragile X ◽  
Gamma Oscillations ◽  
Developmental Trajectory ◽  
Inhibitory Neurons ◽  
Visual Responses ◽  
Age Appropriate ◽  
Eye Opening ◽  
Hyper Sensitivity

Abstract Fragile X syndrome (FXS) is characterized by sensory hyper-sensitivity, and animal models suggest that neuronal hyper-excitability contributes to this phenotype. To understand how sensory dysfunction develops in FXS, we used the rat model (FMR-KO) to quantify the maturation of cortical visual responses from the onset of responsiveness prior to eye-opening, through age equivalents of human juveniles. Rather than hyper-excitability, visual responses before eye-opening had reduced spike rates and an absence of early gamma oscillations, a marker for normal thalamic function at this age. Despite early hypo-excitability, the developmental trajectory of visual responses in FMR-KO rats was normal, and showed the expected loss of visually evoked bursting at the same age as wild-type, two days before eye-opening. At later ages, during the third and fourth post-natal weeks, signs of mild hyper-excitability emerged. These included an increase in the visually-evoked firing of regular spiking, presumptive excitatory, neurons, and a reduced firing of fast-spiking, presumptive inhibitory, neurons. Our results show that early network changes in the FMR-KO rat arise at ages equivalent to fetal humans and have consequences for excitability that are opposite those found in adults. This suggests identification and treatment should begin early, and be tailored in an age-appropriate manner.

scholarly journals Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome

2019 ◽  
Vol 11 (494) ◽  
pp. eaao0498 ◽  
Author(s):  
Antonis Asiminas ◽  
Adam D. Jackson ◽  
Susana R. Louros ◽  
Sally M. Till ◽  
Teresa Spano ◽  
...  
Keyword(s):  
Associative Learning ◽  
Fragile X Syndrome ◽  
Associative Memory ◽  
Rat Model ◽  
Fragile X ◽  
Time Windows ◽  
Treatment Strategies ◽  
Developmental Time ◽  
Developmental Trajectory ◽  
Pharmacological Intervention

Fragile X Syndrome (FXS) is one of the most common monogenic forms of autism and intellectual disability. Preclinical studies in animal models have highlighted the potential of pharmaceutical intervention strategies for alleviating the symptoms of FXS. However, whether treatment strategies can be tailored to developmental time windows that define the emergence of particular phenotypes is unknown. Similarly, whether a brief, early intervention can have long-lasting beneficial effects, even after treatment cessation, is also unknown. To address these questions, we first examined the developmental profile for the acquisition of associative learning in a rat model of FXS. Associative memory was tested using a range of behavioral paradigms that rely on an animal’s innate tendency to explore novelty. Fmr1 knockout (KO) rats showed a developmental delay in their acquisition of object-place recognition and did not demonstrate object-place-context recognition paradigm at any age tested (up to 23 weeks of age). Treatment of Fmr1 KO rats with lovastatin between 5 and 9 weeks of age, during the normal developmental period that this associative memory capability is established, prevents the emergence of deficits but has no effect in wild-type animals. Moreover, we observe no regression of cognitive performance in the FXS rats over several months after treatment. This restoration of the normal developmental trajectory of cognitive function is associated with the sustained rescue of both synaptic plasticity and altered protein synthesis. The findings provide proof of concept that the impaired emergence of the cognitive repertoire in neurodevelopmental disorders may be prevented by brief, early pharmacological intervention.

scholarly journals Disrupted Cortical State Regulation in a Rat Model of Fragile X Syndrome

2016 ◽  
pp. bhv331 ◽  
Author(s):  
Julia Berzhanskaya ◽  
Marnie A. Phillips ◽  
Alexis Gorin ◽  
Chongxi Lai ◽  
Jing Shen ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Rat Model ◽  
Fragile X ◽  
State Regulation

Deletion of Fmr1 in Parvalbumin Inhibitory Neurons Leads to Dysregulated Translation and Selective Behavioral Deficits Associated with Fragile X Syndrome

2021 ◽  
Author(s):  
Magdalena Kalinowska ◽  
Mathijs B. van der Lei ◽  
Michael Kitiashvili ◽  
Maggie Mamcarz ◽  
Mauricio M. Oliveira ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Inhibitory Neurons ◽  
Behavioral Deficits

scholarly journals Developmental trajectory of communication repair in children with Fragile X Syndrome

2020 ◽  
Vol 5 ◽  
pp. 239694152090901 ◽  
Author(s):  
Heather Fielding-Gebhardt ◽  
Steven F Warren ◽  
Nancy C Brady
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Developmental Trajectory

scholarly journals Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Emma K. Baker ◽  
Marta Arpone ◽  
Solange Aliaga Vera ◽  
Lesley Bretherton ◽  
Alexandra Ure ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Abilities ◽  
Fragile X ◽  
Autism Diagnostic Observation Schedule ◽  
Intellectual Functioning ◽  
Autism Spectrum ◽  
Aberrant Behavior Checklist ◽  
Age Appropriate ◽  
Maladaptive Behaviours ◽  
Age And Sex

Abstract Background Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55–199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours. Methods This study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours. Results Comparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. Conclusions Males with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.

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.

Caregiver Reports of Sleep Problems on a Convenience Sample of Children With Fragile X Syndrome

2009 ◽  
Vol 114 (6) ◽  
pp. 383-392 ◽  
Author(s):  
Rebecca Kronk ◽  
Ronald Dahl ◽  
Robert Noll
Keyword(s):  
Fragile X Syndrome ◽  
Assessment Tool ◽  
Sleep Problems ◽  
Fragile X ◽  
Demographic Variables ◽  
Developmental Trajectory ◽  
Sleep Diary ◽  
Sleep Habits ◽  
Convenience Sample ◽  
Children’S Sleep

Abstract Caregivers reported on sleep in a convenience sample of 90 children with fragile X syndrome utilizing a standardized assessment tool, the Children's Sleep Habits Questionnaire (CSHQ), and a 14-day sleep diary. CSHQ data indicated that 47% of participants had sleep problems at a level that suggested referral and further evaluation. Sleep diary data indicated high rates of several sleep problems. These problems did not appear to follow a typical developmental trajectory and were not related to gender or demographic variables. Nineteen percent of the sample was currently receiving medication to improve sleep; however, there were no significant differences between those receiving medications and those not receiving medications.

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