scholarly journals Gamma power abnormalities in a Fmr1-targeted transgenic rat model of fragile X syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Naoki Kozono ◽  
Ai Okamura ◽  
Sokichi Honda ◽  
Mitsuyuki Matsumoto ◽  
Takuma Mihara
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Transgenic Rat ◽  
Preclinical Model ◽  
Alpha Power ◽  
Preclinical Research ◽  
Knock Out ◽  
Gamma Frequency ◽  
Eeg Abnormalities ◽  
Gamma Power

Abstract Fragile X syndrome (FXS) is characteristically displayed intellectual disability, hyperactivity, anxiety, and abnormal sensory processing. Electroencephalography (EEG) abnormalities are also observed in subjects with FXS, with many researchers paying attention to these as biomarkers. Despite intensive preclinical research using Fmr1 knock out (KO) mice, an effective treatment for FXS has yet to be developed. Here, we examined Fmr1-targeted transgenic rats (Fmr1-KO rats) as an alternative preclinical model of FXS. We characterized the EEG phenotypes of Fmr1-KO rats by measuring basal EEG power and auditory steady state response (ASSR) to click trains of stimuli at a frequency of 10–80 Hz. Fmr1-KO rats exhibited reduced basal alpha power and enhanced gamma power, and these rats showed enhanced locomotor activity in novel environment. While ASSR clearly peaked at around 40 Hz, both inter-trial coherence (ITC) and event-related spectral perturbation (ERSP) were significantly reduced at the gamma frequency band in Fmr1-KO rats. Fmr1-KO rats showed gamma power abnormalities and behavioral hyperactivity that were consistent with observations reported in mouse models and subjects with FXS. These results suggest that gamma power abnormalities are a translatable biomarker among species and demonstrate the utility of Fmr1-KO rats for investigating drugs for the treatment of FXS.

scholarly journals Neocortical Localization and Thalamocortical Modulation of Neuronal Hyperexcitability in Fragile X Syndrome

2021 ◽  
Author(s):  
Ernest V. Pedapati ◽  
Lauren M. Schmitt ◽  
Rui Liu ◽  
Lauren E. Ethridge ◽  
Elizabeth Smith ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Gamma Activity ◽  
Neuronal Hyperexcitability ◽  
Gamma Frequency ◽  
Genetic Mosaicism ◽  
Gamma Power ◽  
Relationship Of ◽  
Minimum Norm Estimate

Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key illness features. Translating these findings into patients may identify tractable treatment targets. Using a minimum norm estimate of resting state electroencephalography data, we report novel findings in FXS including: 1) increases in gamma activity across functional networks, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of these abnormalities based on female sex and genetic mosaicism, and 4) relationship of this physiology to intellectual disability and anxiety. Our observations extend findings in Fmr1-/- KO mice to patients with FXS and raise a key role for disrupted thalamocortical modulation in local hyperexcitability, a mechanism that has received limited preclinical attention, but has significant implications for understanding fundamental disease mechanisms.

scholarly journals The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome

2021 ◽  
Author(s):  
Carrie R. Jonak ◽  
Manbir S. Sandhu ◽  
Samantha A. Assad ◽  
Jacqueline A. Barbosa ◽  
Mahindra Makhija ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Eeg Abnormalities

scholarly journals Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability

2021 ◽  
Author(s):  
Carol Wilkinson ◽  
Charles A Nelson
Keyword(s):  
Fragile X Syndrome ◽  
Mouse Models ◽  
Resting State ◽  
Fragile X ◽  
Pearson Correlation ◽  
Language Ability ◽  
Compensatory Mechanisms ◽  
Clinical Biomarkers ◽  
Gamma Power ◽  
Periodic Components

Abstract Background: The lack of robust and reliable clinical biomarkers in Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, has limited the successful translation of bench-to-bedside therapeutics. While numerous drugs have shown promise in reversing synaptic and behavioral phenotypes in mouse models of FXS, none have demonstrated clinical efficacy in humans. Electroencephalographic (EEG) measures have been identified as candidate biomarkers as EEG recordings of both adults with FXS and mouse models of FXS consistently exhibit alterations in resting state and task-related activity. However, the developmental timing of these EEG differences is not known as thus far EEG studies have not focused on young children with FXS. Further, understanding how EEG differences are associated with core symptoms of FXS is crucial to successful use of EEG as a biomarker, and may improve our understanding of the disorder. Methods: Resting-state EEG was collected from FXS boys with full mutation of Fmr1 (2.5-7 years old, n=11) and compared with both age-matched (n=12) and cognitive-matched (n=12) typically developing boys. Power spectra (including aperiodic and periodic components) were compared using non-parametric cluster-based permutation testing. Associations between 30-50Hz gamma power and cognitive, language, and behavioral measures were evaluated using Pearson correlation and linear regression with age as a covariate. Results: FXS participants showed increased power in the beta/gamma range (~25-50Hz) across multiple brain regions. Both a reduction in the aperiodic (1/f) slope and increase in beta/gamma periodic activity contributed to the significant increase in high-frequency power. Increased gamma power, driven by the aperiodic component, was associated with better language ability in the FXS group. No association was observed between gamma power and parent report measures of behavioral challenges, sensory hypersensitivities, or adaptive behaviors. Limitations: The study sample size was small, although comparable to other human studies in rare-genetic disorders. Findings are also limited to males in the age range studied. Conclusions: Resting-state EEG measures from this study in young boys with FXS identified similar increases in gamma power previously reported in adults and mouse models. The observed positive association between resting state aperiodic gamma power and language development supports hypotheses that alterations in some EEG measures may reflect ongoing compensatory mechanisms.

scholarly journals Sex Differences in an Fmr1 Knock‐out Mouse Model of Fragile X Syndrome

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Jessica L. Armstrong ◽  
Yiming Chen ◽  
Tanishka S. Saraf ◽  
Clinton E. Canal
Keyword(s):  
Sex Differences ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Knock Out ◽  
Knock Out Mouse

scholarly journals Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Carlo Brighi ◽  
Federico Salaris ◽  
Alessandro Soloperto ◽  
Federica Cordella ◽  
Silvia Ghirga ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cortical Neurons ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Functional Characterization ◽  
Model Systems ◽  
Network Activity ◽  
Knock Out ◽  
2D And 3D

AbstractFragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models; however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show an increased number of GFAP positive cells, likely astrocytes, increased spontaneous network activity, and depolarizing GABAergic transmission. Cortical brain organoid models show an increased number of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

scholarly journals Baclofen-Associated Neurophysiologic Target Engagement Across Species in Fragile X Syndrome

2021 ◽  
Author(s):  
Carrie R. Jonak ◽  
Ernest V. Pedapati ◽  
Lauren M. Schmitt ◽  
Samantha A. Assad ◽  
Manbir S. Sandhu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Gamma Activity ◽  
Multielectrode Array ◽  
Target Engagement ◽  
Human Experiments ◽  
Gamma Power ◽  
Delayed Language Development

Abstract Background: Fragile X Syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. Methods: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC). Results: In Fmr1 KO mice and in humans with FXS, baclofen use was synchronously associated with suppression of elevated gamma power and increase in theta power at rest. In the Frm1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. Conclusions: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. Trial Registration: The human experiments are registered under NCT02998151.

EEG abnormalities and seizures in genetically diagnosed Fragile X syndrome

2014 ◽  
Vol 38 (1) ◽  
pp. 155-160 ◽  
Author(s):  
Takijah T. Heard ◽  
Sriram Ramgopal ◽  
Jonathan Picker ◽  
Sharyn A. Lincoln ◽  
Alexander Rotenberg ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Eeg Abnormalities

scholarly journals A neurophysiological model of speech production deficits in fragile X syndrome

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Lauren M Schmitt ◽  
Jun Wang ◽  
Ernest V Pedapati ◽  
Angela John Thurman ◽  
Leonard Abbeduto ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Speech Production ◽  
Fragile X ◽  
Expressive Language ◽  
Temporal Cortex ◽  
Autism Spectrum ◽  
Event Related Potential ◽  
Speech Sounds ◽  
Speech Activity ◽  
Gamma Power

Abstract Fragile X syndrome is the most common inherited intellectual disability and monogenic cause of autism spectrum disorder. Expressive language deficits, especially in speech production, are nearly ubiquitous among individuals with fragile X, but understanding of the neurological bases for these deficits remains limited. Speech production depends on feedforward control and the synchronization of neural oscillations between speech-related areas of frontal cortex and auditory areas of temporal cortex. Interaction in this circuitry allows the corollary discharge of intended speech generated from an efference copy of speech commands to be compared against actual speech sounds, which is critical for making adaptive adjustments to optimize future speech. We aimed to determine whether alterations in coherence between frontal and temporal cortices prior to speech production are present in individuals with fragile X and whether they relate to expressive language dysfunction. Twenty-one participants with full-mutation fragile X syndrome (aged 7–55 years, eight females) and 20 healthy controls (matched on age and sex) completed a talk/listen paradigm during high-density EEG recordings. During the talk task, participants repeated pronounced short vocalizations of ‘Ah’ every 1–2 s for a total of 180 s. During the listen task, participants passively listened to their recordings from the talk task. We compared pre-speech event-related potential activity, N1 suppression to speech sounds, single trial gamma power and fronto-temporal coherence between groups during these tasks and examined their relation to performance during a naturalistic language task. Prior to speech production, fragile X participants showed reduced pre-speech negativity, reduced fronto-temporal connectivity and greater frontal gamma power compared to controls. N1 suppression during self-generated speech did not differ between groups. Reduced pre-speech activity and increased frontal gamma power prior to speech production were related to less intelligible speech as well as broader social communication deficits in fragile X syndrome. Our findings indicate that coordinated pre-speech activity between frontal and temporal cortices is disrupted in individuals with fragile X in a clinically relevant way and represents a mechanism contributing to prominent speech production problems in the disorder.

scholarly journals Minocycline Treatment Reverses Sound Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome

2020 ◽  
Vol 14 ◽  
Author(s):  
Jonathan W. Lovelace ◽  
Iryna M. Ethell ◽  
Devin K. Binder ◽  
Khaleel A. Razak
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Minocycline Treatment ◽  
Eeg Abnormalities

scholarly journals CRISPR/Cas9 generated knockout mice lacking phenylalanine hydroxylase protein as a novel preclinical model for human phenylketonuria

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kuldeep Singh ◽  
Cathleen S. Cornell ◽  
Robert Jackson ◽  
Mostafa Kabiri ◽  
Michael Phipps ◽  
...  
Keyword(s):  
Mouse Model ◽  
Phenylalanine Hydroxylase ◽  
Stop Codon ◽  
Body Growth ◽  
Preclinical Model ◽  
Preclinical Research ◽  
Knock Out ◽  
Biochemical Assays ◽  
Pathologic Features ◽  
Age And Sex

AbstractPhenylketonuria (PKU) is an autosomal recessive inborn error of l-phenylalanine (Phe) metabolism. It is caused by a partial or complete deficiency of the enzyme phenylalanine hydroxylase (PAH), which is necessary for conversion of Phe to tyrosine (Tyr). This metabolic error results in buildup of Phe and reduction of Tyr concentration in blood and in the brain, leading to neurological disease and intellectual deficits. Patients exhibit retarded body growth, hypopigmentation, hypocholesterolemia and low levels of neurotransmitters. Here we report first attempt at creating a homozygous Pah knock-out (KO) (Hom) mouse model, which was developed in the C57BL/6 J strain using CRISPR/Cas9 where codon 7 (GAG) in Pah gene was changed to a stop codon TAG. We investigated 2 to 6-month-old, male, Hom mice using comprehensive behavioral and biochemical assays, MRI and histopathology. Age and sex-matched heterozygous Pah-KO (Het) mice were used as control mice, as they exhibit enough PAH enzyme activity to provide Phe and Tyr levels comparable to the wild-type mice. Overall, our findings demonstrate that 6-month-old, male Hom mice completely lack PAH enzyme, exhibit significantly higher blood and brain Phe levels, lower levels of brain Tyr and neurotransmitters along with lower myelin content and have significant behavioral deficit. These mice exhibit phenotypes that closely resemble PKU patients such as retarded body growth, cutaneous hypopigmentation, and hypocholesterolemia when compared to the age- and sex-matched Het mice. Altogether, biochemical, behavioral, and pathologic features of this novel mouse model suggest that it can be used as a reliable translational tool for PKU preclinical research and drug development.

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