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 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.

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 The GABAA Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome

2011 ◽  
Vol 33 (5) ◽  
pp. 395-403 ◽  
Author(s):  
Jose Luis Olmos-Serrano ◽  
Joshua G. Corbin ◽  
Mark P. Burns
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Receptor Agonist ◽  
Fragile X ◽  
Behavioral Deficits

scholarly journals Imbalance of Neocortical Excitation and Inhibition and Altered UP States Reflect Network Hyperexcitability in the Mouse Model of Fragile X Syndrome

2008 ◽  
Vol 100 (5) ◽  
pp. 2615-2626 ◽  
Author(s):  
Jay R. Gibson ◽  
Aundrea F. Bartley ◽  
Seth A. Hays ◽  
Kimberly M. Huber
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Barrel Cortex ◽  
Feedback Inhibition ◽  
Fragile X ◽  
Inhibitory Neurons ◽  
Neurological Deficits ◽  
Membrane Excitability ◽  
Up States ◽  
Layer 4

Despite the pronounced neurological deficits associated with mental retardation and autism, it is unknown if altered neocortical circuit function occurs in these prevalent disorders. Here we demonstrate specific alterations in local synaptic connections, membrane excitability, and circuit activity of defined neuron types in sensory neocortex of the mouse model of Fragile X Syndrome—the Fmr1 knockout (KO). Overall, these alterations result in hyperexcitability of neocortical circuits in the Fmr1 KO. Specifically, we observe a substantial deficit in local excitatory drive (∼50%) targeting fast-spiking (FS) inhibitory neurons in layer 4 of somatosensory, barrel cortex. This persists until at least 4 wk of age suggesting it may be permanent. In contrast, monosynaptic GABAergic synaptic transmission was unaffected. Overall, these changes indicate that local feedback inhibition in neocortical layer 4 is severely impaired in the Fmr1 KO mouse. An increase in the intrinsic membrane excitability of excitatory neurons may further contribute to hyperexcitability of cortical networks. In support of this idea, persistent neocortical circuit activity, or UP states, elicited by thalamic stimulation was longer in duration in the Fmr1 KO mouse. In addition, network inhibition during the UP state was less synchronous, including a 14% decrease in synchrony in the gamma frequency range (30–80 Hz). These circuit changes may be involved in sensory stimulus hypersensitivity, epilepsy, and cognitive impairment associated with Fragile X and autism.

Living with Fragile X Syndrome

2017 ◽  
Author(s):  
◽  
Rebecca Schira ◽  
Samantha Alexander ◽  
Noelani Brisbane ◽  
Kaitlyn Williams
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X

Fragile X Syndrome and Family Occupations

2019 ◽  
Author(s):  
Decerie Mendoza ◽  
Tracy Ye ◽  
Martina Dualan ◽  
Elena Javier
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X
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