Normal CA1 place fields but discoordinated network discharge in a Fmr1-null mouse model of fragile X syndrome

SummarySilence of FMR1 causes loss of fragile X mental retardation protein (FMRP) and dysregulated translation at synapses, resulting in the intellectual disability and autistic symptoms of Fragile X Syndrome (FXS). Synaptic dysfunction hypotheses for how intellectual disabilities like cognitive inflexibility arise in FXS, predict impaired neural coding in the absence of FMRP. We tested the prediction by comparing hippocampus place cells in wild-type and FXS-model mice. Experience-driven CA1 synaptic function and synaptic plasticity changes are excessive in Fmr1-null mice, but CA1 place fields are normal. However, Fmr1-null discharge relationships to local field potential oscillations are abnormally weak, stereotyped, and homogeneous; also discharge coordination within Fmr1-null place cell networks is weaker and less reliable than wild-type. Rather than disruption of single-cell neural codes, these findings point to invariant tuning of single-cell responses and inadequate discharge coordination within neural ensembles as a pathophysiological basis of cognitive inflexibility in FXS.

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Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1

10.1101/152488 ◽

2017 ◽

Author(s):

Dino Dvorak ◽

Basma Radwan ◽

Fraser T. Sparks ◽

Zoe Nicole Talbot ◽

André A. Fenton

Keyword(s):

Fragile X Syndrome ◽

Cognitive Deficits ◽

Pyramidal Cell ◽

Fragile X ◽

Avoidance Task ◽

Cognitive Variables ◽

Wild Type ◽

Cognitive Inflexibility ◽

Place Avoidance ◽

Shock Zone

ABSTRACTBehavior is used to assess memory and cognitive deficits in animals like Fmrl-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal CA1 hippocampus. During a shocked-place avoidance task, slow gamma (SG: 30-50 Hz) dominates mid-frequency gamma (MG: 70-90 Hz) oscillations 2-3 seconds before successful avoidance, but not failures. Wild-type but not Fmrl-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdominance) decrease in wild-type but not in cognitively inflexible Fmrl-null mice. During SGdominance, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, wild-type ensembles represent distant locations near the currently-correct shock zone but Fmrl-null ensembles represent the formerly-correct zone. These findings indicate that recollection occurs when CA1 slow gamma dominates mid-frequency gamma, and that accurate recollection of inappropriate memories explains Fmrl-null cognitive inflexibility.

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Normal CA1 Place Fields but Discoordinated Network Discharge in a Fmr1-Null Mouse Model of Fragile X Syndrome

Neuron ◽

10.1016/j.neuron.2017.12.043 ◽

2018 ◽

Vol 97 (3) ◽

pp. 684-697.e4 ◽

Cited By ~ 22

Author(s):

Zoe Nicole Talbot ◽

Fraser Todd Sparks ◽

Dino Dvorak ◽

Bridget Mary Curran ◽

Juan Marcos Alarcon ◽

...

Keyword(s):

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Null Mouse ◽

Place Fields

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GABA Measurement in a Neonatal Fragile X Syndrome Mouse Model Using 1H-Magnetic Resonance Spectroscopy and Mass Spectrometry

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.612685 ◽

2020 ◽

Vol 13 ◽

Author(s):

Samantha T. Reyes ◽

Sanaz Mohajeri ◽

Karolina Krasinska ◽

Scarlett G. Guo ◽

Meng Gu ◽

...

Keyword(s):

Mass Spectrometry ◽

Magnetic Resonance ◽

Frontal Cortex ◽

Fragile X Syndrome ◽

Knockout Mice ◽

Fragile X ◽

Gabaergic System ◽

Wild Type ◽

Gaba Concentration ◽

Non Invasive

Fragile X syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder and inherited cause of intellectual disability that affects approximately one in 7,000 males and one in 11,000 females. In FXS, the Fmr1 gene is silenced and prevents the expression of the fragile X mental retardation protein (FMRP) that directly targets mRNA transcripts of multiple GABAA subunits. Therefore, FMRP loss adversely impacts the neuronal firing of the GABAergic system which creates an imbalance in the excitatory/inhibitory ratio within the brain. Current FXS treatment strategies focus on curing symptoms, such as anxiety or decreased social function. While treating symptoms can be helpful, incorporating non-invasive imaging to evaluate how treatments change the brain’s biology may explain what molecular aberrations are associated with disease pathology. Thus, the GABAergic system is suitable to explore developing novel therapeutic strategies for FXS. To understand how the GABAergic system may be affected by this loss-of-function mutation, GABA concentrations were examined within the frontal cortex and thalamus of 5-day-old wild type and Fmr1 knockout mice using both 1H magnetic resonance imaging (1H-MRS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our objective was to develop a reliable scanning method for neonatal mice in vivo and evaluate whether 1H-MRS is suitable to capture regional GABA concentration differences at the front end of the critical cortical period where abnormal neurodevelopment occurs due to FMRP loss is first detected. 1H-MRS quantified GABA concentrations in both frontal cortex and thalamus of wild type and Fmr1 knockout mice. To substantiate the results of our 1H-MRS studies, in vitro LC-MS/MS was also performed on brain homogenates from age-matched mice. We found significant changes in GABA concentration between the frontal cortex and thalamus within each mouse from both wild type and Fmr1 knockout mice using 1H-MRS and LC-MS/MS. Significant GABA levels were also detected in these same regions between wild type and Fmr1 knockout mice by LC-MS/MS, validating that FMRP loss directly affects the GABAergic system. Thus, these new findings support the need to develop an effective non-invasive imaging method to monitor novel GABAergic strategies aimed at treating patients with FXS.

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Corrigendum to “Modulation of dendritic spines and synaptic function by Rac1: A possible link to fragile X syndrome pathology” [Brain Res. 1399 (2011) 79–95]

Brain Research ◽

10.1016/j.brainres.2011.09.027 ◽

2011 ◽

Vol 1423 ◽

pp. 114-115

Author(s):

Odelia Y.N. Bongmba ◽

Luis A. Martinez ◽

Mary E. Elhardt ◽

Karlis Butler ◽

Maria V. Tejada-Simon

Keyword(s):

Fragile X Syndrome ◽

Dendritic Spines ◽

Fragile X ◽

Synaptic Function

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Aberrant Rac1-cofilin signaling mediates defects in dendritic spines, synaptic function, and sensory perception in fragile X syndrome

Science Signaling ◽

10.1126/scisignal.aan0852 ◽

2017 ◽

Vol 10 (504) ◽

pp. eaan0852 ◽

Cited By ~ 38

Author(s):

Alexander Pyronneau ◽

Qionger He ◽

Jee-Yeon Hwang ◽

Morgan Porch ◽

Anis Contractor ◽

...

Keyword(s):

Fragile X Syndrome ◽

Dendritic Spines ◽

Fragile X ◽

Sensory Perception ◽

Synaptic Function

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Detection of long repeat expansions from PCR-free whole-genome sequence data

10.1101/093831 ◽

2016 ◽

Cited By ~ 3

Author(s):

Egor Dolzhenko ◽

Joke J.F.A. van Vugt ◽

Richard J. Shaw ◽

Mitchell A. Bekritsky ◽

Marka van Blitterswijk ◽

...

Keyword(s):

Fragile X Syndrome ◽

Sequence Data ◽

Fragile X ◽

Software Tool ◽

Whole Genome Sequence ◽

Read Length ◽

Whole Genome ◽

Wild Type ◽

Short Read ◽

Repeat Expansions

AbstractIdentifying large repeat expansions such as those that cause amyotrophic lateral sclerosis (ALS) and Fragile X syndrome is challenging for short-read (100-150 bp) whole genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3,001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Taking the RP-PCR calls as the ground truth, our WGS-based method identified pathogenic repeat expansions with 98.1% sensitivity and 99.7% specificity. Further inspection identified that all 11 conflicts were resolved as errors in the original RP-PCR results. Compared against this updated result, ExpansionHunter correctly classified all (212/212) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2,786/2,789) of the wild type samples were correctly classified as wild type by this method with the remaining two identified as possible expansions. We further applied our algorithm to a set of 144 samples where every sample had one of eight different pathogenic repeat expansions including examples associated with fragile X syndrome, Friedreich’s ataxia and Huntington’s disease and correctly flagged all of the known repeat expansions. Finally, we tested the accuracy of our method for short repeats by comparing our genotypes with results from 860 samples sized using fragment length analysis and determined that our calls were >95% accurate. ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.

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Faculty Opinions recommendation of Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1162995.623635 ◽

2009 ◽

Author(s):

Leslie Thompson

Keyword(s):

Mental Retardation ◽

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Synaptic Function ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein

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FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

eLife ◽

10.7554/elife.52621 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 6

Author(s):

Raeann Goering ◽

Laura I Hudish ◽

Bryan B Guzman ◽

Nisha Raj ◽

Gary J Bassell ◽

...

Keyword(s):

Fragile X Syndrome ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Fragile X ◽

Rna Localization ◽

Null Mouse ◽

Rna Sequences ◽

Rna Molecules ◽

G Quadruplex

The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

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