scholarly journals Altered brain-wide auditory networks in a zebrafish model of fragile X syndrome

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Lena Constantin ◽  
Rebecca E. Poulsen ◽  
Leandro A. Scholz ◽  
Itia A. Favre-Bulle ◽  
Michael A. Taylor ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Visual Motion ◽  
Fragile X ◽  
Auditory Pathway ◽  
Brain Regions ◽  
Torus Semicircularis ◽  
Auditory Stimuli ◽  
Auditory Information ◽  
Zebrafish Model ◽  
Cellular Resolution

Abstract Background Loss or disrupted expression of the FMR1 gene causes fragile X syndrome (FXS), the most common monogenetic form of autism in humans. Although disruptions in sensory processing are core traits of FXS and autism, the neural underpinnings of these phenotypes are poorly understood. Using calcium imaging to record from the entire brain at cellular resolution, we investigated neuronal responses to visual and auditory stimuli in larval zebrafish, using fmr1 mutants to model FXS. The purpose of this study was to model the alterations of sensory networks, brain-wide and at cellular resolution, that underlie the sensory aspects of FXS and autism. Results Combining functional analyses with the neurons’ anatomical positions, we found that fmr1−/− animals have normal responses to visual motion. However, there were several alterations in the auditory processing of fmr1−/− animals. Auditory responses were more plentiful in hindbrain structures and in the thalamus. The thalamus, torus semicircularis, and tegmentum had clusters of neurons that responded more strongly to auditory stimuli in fmr1−/− animals. Functional connectivity networks showed more inter-regional connectivity at lower sound intensities (a − 3 to − 6 dB shift) in fmr1−/− larvae compared to wild type. Finally, the decoding capacities of specific components of the ascending auditory pathway were altered: the octavolateralis nucleus within the hindbrain had significantly stronger decoding of auditory amplitude while the telencephalon had weaker decoding in fmr1−/− mutants. Conclusions We demonstrated that fmr1−/− larvae are hypersensitive to sound, with a 3–6 dB shift in sensitivity, and identified four sub-cortical brain regions with more plentiful responses and/or greater response strengths to auditory stimuli. We also constructed an experimentally supported model of how auditory information may be processed brain-wide in fmr1−/− larvae. Our model suggests that the early ascending auditory pathway transmits more auditory information, with less filtering and modulation, in this model of FXS.

scholarly journals Behavioral and Synaptic Circuit Features in a Zebrafish Model of Fragile X Syndrome

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e51456 ◽  
Author(s):  
Ming-Chong Ng ◽  
Yi-Ling Yang ◽  
Kwok-Tung Lu
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Zebrafish Model ◽  
Synaptic Circuit

scholarly journals Altered brain-wide auditory networks in fmr1-mutant larval zebrafish

2019 ◽  
Author(s):  
Lena Constantin ◽  
Rebecca E. Poulsen ◽  
Itia A. Favre-Bulle ◽  
Michael A. Taylor ◽  
Biao Sun ◽  
...  
Keyword(s):  
Graph Theory ◽  
Sensory Processing ◽  
Calcium Imaging ◽  
Fragile X ◽  
Auditory Information ◽  
Wild Type ◽  
Larval Zebrafish ◽  
Cellular Resolution ◽  
Psychiatric Conditions ◽  
Functional Analyses

Altered sensory processing is characteristic of several psychiatric conditions, including autism and fragile X syndrome (FXS). Here, we use whole-brain calcium imaging at cellular resolution to map sensory processing in wild type larval zebrafish and mutants for fmr1, which causes FXS in humans. Using functional analyses and graph theory, we describe increased transmission and reduced filtering of auditory information, resulting in network-wide hypersensitivity analogous to the auditory phenotypes seen in FXS.

scholarly journals Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Karen Kelley ◽  
Shin-Ju E. Chang ◽  
Shi-Lung Lin
Keyword(s):  
Fragile X Syndrome ◽  
Metabotropic Glutamate Receptor ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Protein Product ◽  
Repeat Expansion ◽  
Trinucleotide Repeats ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Triplet Repeat Expansion

The majority of the human genome is comprised of non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs) such as fragile X syndrome (FXS). After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed byDicerendoribonuclases to form microRNA (miRNA)-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs) is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced DNA methylation of theFMR15′-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptionalFMR1gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, whileFMR1inactivation augments metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD), leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.

scholarly journals Hyperexcitability and Homeostasis in Fragile X Syndrome

2022 ◽  
Vol 14 ◽  
Author(s):  
Xiaopeng Liu ◽  
Vipendra Kumar ◽  
Nien-Pei Tsai ◽  
Benjamin D. Auerbach
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Inhibitory Neuron ◽  
Cell Types ◽  
Developmental Time ◽  
Brain Regions ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Neuron Activity ◽  
The Impact

Fragile X Syndrome (FXS) is a leading inherited cause of autism and intellectual disability, resulting from a mutation in the FMR1 gene and subsequent loss of its protein product FMRP. Despite this simple genetic origin, FXS is a phenotypically complex disorder with a range of physical and neurocognitive disruptions. While numerous molecular and cellular pathways are affected by FMRP loss, there is growing evidence that circuit hyperexcitability may be a common convergence point that can account for many of the wide-ranging phenotypes seen in FXS. The mechanisms for hyperexcitability in FXS include alterations to excitatory synaptic function and connectivity, reduced inhibitory neuron activity, as well as changes to ion channel expression and conductance. However, understanding the impact of FMR1 mutation on circuit function is complicated by the inherent plasticity in neural circuits, which display an array of homeostatic mechanisms to maintain activity near set levels. FMRP is also an important regulator of activity-dependent plasticity in the brain, meaning that dysregulated plasticity can be both a cause and consequence of hyperexcitable networks in FXS. This makes it difficult to separate the direct effects of FMR1 mutation from the myriad and pleiotropic compensatory changes associated with it, both of which are likely to contribute to FXS pathophysiology. Here we will: (1) review evidence for hyperexcitability and homeostatic plasticity phenotypes in FXS models, focusing on similarities/differences across brain regions, cell-types, and developmental time points; (2) examine how excitability and plasticity disruptions interact with each other to ultimately contribute to circuit dysfunction in FXS; and (3) discuss how these synaptic and circuit deficits contribute to disease-relevant behavioral phenotypes like epilepsy and sensory hypersensitivity. Through this discussion of where the current field stands, we aim to introduce perspectives moving forward in FXS research.

scholarly journals Cardiovascular and Behavioral Response to Auditory Stimuli in Boys With Fragile X Syndrome

2012 ◽  
Vol 38 (3) ◽  
pp. 276-284 ◽  
Author(s):  
J. E. Roberts ◽  
A. C. J. Long ◽  
L. M. McCary ◽  
A. N. Quady ◽  
B. S. Rose ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Behavioral Response ◽  
Fragile X ◽  
Auditory Stimuli

scholarly journals Altered Cerebral Protein Synthesis in Fragile X Syndrome: Studies in Human Subjects and Knockout Mice

2013 ◽  
Vol 33 (4) ◽  
pp. 499-507 ◽  
Author(s):  
Mei Qin ◽  
Kathleen C Schmidt ◽  
Alan J Zametkin ◽  
Shrinivas Bishu ◽  
Lisa M Horowitz ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Human Subjects ◽  
Brain Regions ◽  
Synaptic Activity ◽  
Whole Brain ◽  
Propofol Sedation ◽  
Positron Emission ◽  
Cerebral Protein Synthesis

Dysregulated protein synthesis is thought to be a core phenotype of fragile X syndrome (FXS). In a mouse model ( Fmr1 knockout (KO)) of FXS, rates of cerebral protein synthesis (rCPS) are increased in selective brain regions. We hypothesized that rCPS are also increased in FXS subjects. We measured rCPS with the L-[1-11C]leucine positron emission tomography (PET) method in whole brain and 10 regions in 15 FXS subjects who, because of their impairments, were studied under deep sedation with propofol. We compared results with those of 12 age-matched controls studied both awake and sedated. In controls, we found no differences in rCPS between awake and propofol sedation. Contrary to our hypothesis, FXS subjects under propofol sedation had reduced rCPS in whole brain, cerebellum, and cortex compared with sedated controls. To investigate whether propofol could have a disparate effect in FXS subjects masking usually elevated rCPS, we measured rCPS in C57Bl/6 wild-type (WT) and KO mice awake or under propofol sedation. Propofol decreased rCPS substantially in most regions examined in KO mice, but in WT mice caused few discrete changes. Propofol acts by decreasing neuronal activity either directly or by increasing inhibitory synaptic activity. Our results suggest that changes in synaptic signaling can correct increased rCPS in FXS.

scholarly journals Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome

2020 ◽  
Vol 10 (12) ◽  
pp. 899
Author(s):  
James R. Brašić ◽  
Ayon Nandi ◽  
David S. Russell ◽  
Danna Jennings ◽  
Olivier Barret ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Brain Regions ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Positron Emission ◽  
Subcortical Regions

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) in fmr1 knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR5 expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR5 density as a proxy of mGluR5 expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluR5s. The density and the distribution of mGluR5 were measured in two independent samples of men with FXS (N = 9) and typical development (TD) (N = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR5 expression showed that mGluR5 expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.

scholarly journals 120 Fragile X Syndrome Sharing Similar Neural Network Abnormalities as ADHD

CNS Spectrums ◽  
2018 ◽  
Vol 23 (1) ◽  
pp. 76-76
Author(s):  
Chunhui Yang ◽  
Carolyn Beebe Smith ◽  
Guoqiang Xing ◽  
Sandeep Gaonkar
Keyword(s):  
Neural Network ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Rna Binding ◽  
Psychiatric Symptoms ◽  
Fragile X ◽  
Brain Regions ◽  
Brain Maturation ◽  
Null Mouse ◽  
Study Objective

AbstractTitleFragile X syndrome sharing similar neural network abnormalities as ADHDStudy Objective(s)The Fragile X syndrome (FXS) phenotype typically involves a variety of psychiatric symptoms, including features of autism, attention deficit/hyperactivity disorder (ADHD), anxiety, and aggression. Studies have shown that ADHD is characterized by multiple functional and structural neural network abnormalities including fronto-striatal, fronto-parieto-temporal, fronto-cerebellar and fronto-limbic networks (Rubia, 2014; Norman, 2017). Studies have shown that ADHD is characterized by a delay in structural brain maturation (Rubia, 2007). Absence of the FMR1 gene product Fragile X mental retardation protein (FMRP) results in FXS, an inherited form of mental retardation. FMRP is an RNA binding protein functioning as a nucleocytoplasmic shuttling. In a knockout mouse model of FXS (Fmr1 null), Qin, et al showed regionally selective effects on cerebral metabolic rates for glucose (rCMRglc) (Qin, 2002) and rates of cerebral protein synthesis (Qin, 2005). In the present study, we asked if there is a relationship between brain regions most vulnerable to the effects of the absence of FMRP in the Fmr1 null mouse, and if the distribution consistent with the structural and functional brain abnormalities in ADHD. We also asked if there is a difference between males and females in the regional distributions and the levels of the FXR mRNAs.MethodWe used 35S-labeled probes specific for the mRNAs to perform in situ hybridization on brains from male (n=4) and female (n=4) mice at 6 months of age. Flowing hybridization, brain sections were exposed to X-ray film and optical density were measured in nine brain regions on autoradiograms of sections hybridized to the probe.ResultsThe highest levels of expression we observed were in the cerebellum, granular layers of the hippocampus. Levels of expression were also high in CA1 pyramidal neurons of hippocampus, amygdala and granule layer of olfactory bulb. We found intermediate levels in the anterior hypothalamus and in cingulate and frontal cortex. Low levels of expression were found in thalamus and caudate. The distribution for the probe was similar in male and female mice, but we found a tendency for male mice to have higher levels than females.Funding AcknowledgementsNo funding.

scholarly journals Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala

2014 ◽  
Vol 112 (4) ◽  
pp. 890-902 ◽  
Author(s):  
Brandon S. Martin ◽  
Joshua G. Corbin ◽  
Molly M. Huntsman
Keyword(s):  
Intellectual Disability ◽  
Patch Clamp ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Basolateral Amygdala ◽  
Fragile X ◽  
Brain Regions ◽  
Wild Type ◽  
Gabaergic Transmission ◽  
Whole Cell Patch Clamp

Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability. Comorbidities of FXS such as autism are increasingly linked to imbalances in excitation and inhibition (E/I) as well as dysfunction in GABAergic transmission in a number of brain regions including the amygdala. However, the link between E/I imbalance and GABAergic transmission deficits in the FXS amygdala is poorly understood. Here we reveal that normal tonic GABAA receptor-mediated neurotransmission in principal neurons (PNs) of the basolateral amygdala (BLA) is comprised of both δ- and α5-subunit-containing GABAA receptors. Furthermore, tonic GABAergic capacity is reduced in these neurons in the Fmr1 knockout (KO) mouse model of FXS (1.5-fold total, 3-fold δ-subunit, and 2-fold α5-subunit mediated) as indicated by application of gabazine (50 μM), 4,5,6,7-tetrahydroisoxazolo[5,4- c]pyridin-3-ol (THIP, 1 μM), and α5ia (1.5 μM) in whole cell patch-clamp recordings. Moreover, α5-containing tonic GABAA receptors appear to preferentially modulate nonsomatic compartments of BLA PNs. Examination of evoked feedforward synaptic transmission in these cells surprisingly revealed no differences in overall synaptic conductance or E/I balance between wild-type (WT) and Fmr1 KO mice. Instead, we observed altered feedforward kinetics in Fmr1 KO PNs that supports a subtle yet significant decrease in E/I balance at the peak of excitatory conductance. Blockade of α5-subunit-containing GABAA receptors replicated this condition in WT PNs. Therefore, our data suggest that tonic GABAA receptor-mediated neurotransmission can modulate synaptic E/I balance and timing established by feedforward inhibition and thus may represent a therapeutic target to enhance amygdala function in FXS.

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