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

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.

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

2017 ◽  
Author(s):  
Fraser Todd Sparks ◽  
Zoe Nicole Talbot ◽  
Dino Dvorak ◽  
Bridget Mary Curran ◽  
Juan Marcos Alarcon ◽  
...  
Keyword(s):  
Single Cell ◽  
Fragile X Syndrome ◽  
Neural Coding ◽  
Fragile X ◽  
Field Potential ◽  
Synaptic Function ◽  
Null Mouse ◽  
Wild Type ◽  
Place Fields ◽  
Cognitive Inflexibility

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.

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

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.

scholarly journals 116.1 GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Some Cognitive Deficits in a Fragile X Syndrome Mouse Model

2017 ◽  
Vol 43 (suppl_1) ◽  
pp. S62-S62
Author(s):  
Steven Siegel ◽  
Dunan Sinclair ◽  
Mitsuyuki Matsumoto ◽  
Robert Featherstone ◽  
Olya Melnechenko ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Neural Oscillations

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

2016 ◽  
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.

scholarly journals Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

2022 ◽  
Author(s):  
Sahar Javadi ◽  
Yue Li ◽  
Jie Shen ◽  
Lucy Zhao ◽  
Yao Fu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Young Adult ◽  
Neural Stem Cells ◽  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Fragile X ◽  
Therapeutic Effects ◽  
Mature Adult ◽  
Mature Adults ◽  
Deficient Mice

Background: Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic form of autism, is caused by a loss of FMRP translational regulator 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects. Methods: We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying persistent effects of Nutlin-3, we analyzed proliferation and differentiation of neural stem cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice. Results: We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6-month of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to extracellular matrix, secreted factors, and cell membrane proteins in FMR1-deficient hippocampus.

scholarly journals Higher Doses of (+)MK-801 (Dizocilpine) Induced Mortality and Procedural but Not Cognitive Deficits in Delayed Testing in the Active Place Avoidance With Reversal on the Carousel

2015 ◽  
pp. 269-275
Author(s):  
E. BRICHTOVÁ ◽  
T. PETRÁSEK ◽  
K. VALEŠ ◽  
A. STUCHLÍK
Keyword(s):  
Cognitive Deficits ◽  
High Dose ◽  
Avoidance Task ◽  
Breeding Colony ◽  
Mk 801 ◽  
Place Avoidance ◽  
Long Evans ◽  
Higher Doses ◽  
Systemic Application ◽  
Significant Mortality

Schizophrenia is a devastating disorder affecting 1 % of the world's population. An important role in the study of this disease is played by animal models. Since there is evidence that acute psychotic episodes can have consequences on later cognitive functioning, the present study has investigated the effects of a single systemic application of higher doses of (+)MK-801 (3 mg/kg and 5 mg/kg) to adult male Long-Evans rats from the Institute’s breeding colony on delayed testing in the active place avoidance task with reversal on the Carousel (a rotating arena). Besides significant mortality due to the injections, a disruption of procedural functions in active place avoidance, after the dose 5 mg/kg was observed. It was concluded that Long-Evans rats from our breeding colony do not represent a suitable biomodel for studying the effects of single high-dose NMDA antagonists.

Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders

2019 ◽  
Vol 70 (1) ◽  
pp. 167-181 ◽  
Author(s):  
Ilse Gantois ◽  
Jelena Popic ◽  
Arkady Khoutorsky ◽  
Nahum Sonenberg
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Neurological Disorders ◽  
Fragile X ◽  
Autism Spectrum ◽  
Cellular Models ◽  
The Us ◽  
Mental Retardation Protein ◽  
Drug Treatments ◽  
Core Symptoms

Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.

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