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.

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 Deletion of Fmr1 from Forebrain Excitatory Neurons Triggers Abnormal Cellular, EEG, and Behavioral Phenotypes in the Auditory Cortex of a Mouse Model of Fragile X Syndrome

2019 ◽  
Vol 30 (3) ◽  
pp. 969-988 ◽  
Author(s):  
Jonathan W Lovelace ◽  
Maham Rais ◽  
Arnold R Palacios ◽  
Xinghao S Shuai ◽  
Steven Bishay ◽  
...  
Keyword(s):  
Mouse Model ◽  
Auditory Cortex ◽  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Behavioral Phenotypes ◽  
Excitatory Neurons ◽  
Gamma Power ◽  
Processing Deficits

Abstract Fragile X syndrome (FXS) is a leading genetic cause of autism with symptoms that include sensory processing deficits. In both humans with FXS and a mouse model [Fmr1 knockout (KO) mouse], electroencephalographic (EEG) recordings show enhanced resting state gamma power and reduced sound-evoked gamma synchrony. We previously showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to these phenotypes by affecting perineuronal nets (PNNs) around parvalbumin (PV) interneurons in the auditory cortex of Fmr1 KO mice. However, how different cell types within local cortical circuits contribute to these deficits is not known. Here, we examined whether Fmr1 deletion in forebrain excitatory neurons affects neural oscillations, MMP-9 activity, and PV/PNN expression in the auditory cortex. We found that cortical MMP-9 gelatinase activity, mTOR/Akt phosphorylation, and resting EEG gamma power were enhanced in CreNex1/Fmr1Flox/y conditional KO (cKO) mice, whereas the density of PV/PNN cells was reduced. The CreNex1/Fmr1Flox/y cKO mice also show increased locomotor activity, but not the anxiety-like behaviors. These results indicate that fragile X mental retardation protein changes in excitatory neurons in the cortex are sufficient to elicit cellular, electrophysiological, and behavioral phenotypes in Fmr1 KO mice. More broadly, these results indicate that local cortical circuit abnormalities contribute to sensory processing deficits in autism spectrum disorders.

scholarly journals Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome

2020 ◽  
Vol 10 (6) ◽  
pp. 361
Author(s):  
Mittal Jasoliya ◽  
Heather Bowling ◽  
Ignacio Cortina Petrasic ◽  
Blythe Durbin-Johnson ◽  
Eric Klann ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Drug Response ◽  
Molecular Level ◽  
Fragile X ◽  
Primary Objective ◽  
Molecular Biomarkers ◽  
Target Engagement ◽  
Targeted Treatments ◽  
Expression Abundance ◽  
Metalloproteinase 9

Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs’ response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self-reported improvement in clinical phenotypes (CGI-I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.

scholarly journals Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

2019 ◽  
Vol 13 ◽  
Author(s):  
Chloé Felgerolle ◽  
Betty Hébert ◽  
Maryvonne Ardourel ◽  
Géraldine Meyer-Dilhet ◽  
Arnaud Menuet ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Visual Behavior

scholarly journals Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome

2020 ◽  
Vol 10 (4) ◽  
pp. 239
Author(s):  
Debra L. Reisinger ◽  
Rebecca C. Shaffer ◽  
Nicole Tartaglia ◽  
Elizabeth Berry-Kravis ◽  
Craig A. Erickson
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Motor Behaviors ◽  
Sensory Motor ◽  
Adolescents And Adults ◽  
Males And Females ◽  
The Impact

Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence; however, little is known about the subtypes of RRBs in adolescents and adults. Further, literature on the RRB profile of females with FXS is limited. The present study examines the RRB profile across subtypes and specific items in both males and females with FXS while assessing for differences based on age, ASD diagnosis and the impact of IQ. Participants included 154 individuals with FXS (ages 2 to 50 years old). Results revealed a peak in RRB severity in FXS between 7–12 years for the majority of RRB subscales with the exception of Sensory-Motor behaviors peaking between 2 and 12 years before declining. Distinct RRB profiles in males and females with FXS emerged in addition to significant overlap among the item and subscale levels of RRBs across gender. Further, an added diagnosis of ASD significantly increased rates of RRBs across all subscale levels, but not necessarily across all items. Lastly, IQ did not solely account for the presence of RRBs in FXS, with Sensory-Motor behaviors being driven by comorbid ASD in males with FXS, and Restricted Interest behaviors being driven by comorbid ASD regardless of gender. These findings build on the current understanding of RRBs in FXS based on gender and comorbid ASD and lay important groundwork for the development of targeted behavioral and pharmacological treatments.

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 Multielectrode array analysis of EEG biomarkers in a mouse model of Fragile X Syndrome

2020 ◽  
Vol 138 ◽  
pp. 104794 ◽  
Author(s):  
Carrie R. Jonak ◽  
Jonathan W. Lovelace ◽  
Iryna M. Ethell ◽  
Khaleel A. Razak ◽  
Devin K. Binder
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Multielectrode Array ◽  
Array Analysis

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.

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