Acute administration of NLX-101, a Serotonin 1A receptor agonist, improves auditory temporal processing during development in a mouse model of Fragile X Syndrome / Xin TAO in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Acute administration of NLX-101, a Serotonin 1A receptor agonist, improves auditory temporal processing during development in a mouse model of Fragile X Syndrome Type de document : texte imprimé Auteurs : Xin TAO, Auteur ; Katilynne CROOM, Auteur ; Adrian NEWMAN-TANCREDI, Auteur ; Mark VARNEY, Auteur ; Khaleel A. RAZAK, Auteur Langues : Anglais (eng) Mots-clés : Animals  Fragile X Syndrome/physiopathology  Disease Models, Animal  Mice, Knockout  Mice  Fragile X Mental Retardation Protein/genetics  Male  Electroencephalography  Serotonin 5-HT1 Receptor Agonists/pharmacology/administration & dosage  Auditory Perception/drug effects/physiology  Female  Mice, Inbred C57BL  Evoked Potentials, Auditory/drug effects/physiology  5-HT1A receptors  Autism spectrum disorders  Fragile X syndrome  Sensory hypersensitivity  Serotonin  Speech processing  Temporal processing  by Institutional Animal Care and Use Committee at the University of California,  Riverside. Consent for publication: Not applicable. Competing interests: MV &  AN-T are Shareholders in Neurolixis. Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a leading known genetic cause of intellectual disability and autism spectrum disorders (ASD)-associated behaviors. A consistent and debilitating phenotype of FXS is auditory hypersensitivity that may lead to delayed language and high anxiety. Consistent with findings in FXS human studies, the mouse model of FXS, the Fmr1 knock out (KO) mouse, shows auditory hypersensitivity and temporal processing deficits. In electroencephalograph (EEG) recordings from humans and mice, these deficits manifest as increased N1 amplitudes in event-related potentials (ERP), increased gamma band single trial power (STP) and reduced phase locking to rapid temporal modulations of sound. In our previous study, we found that administration of the selective serotonin-1 A (5-HT(1A))receptor biased agonist, NLX-101, protected Fmr1 KO mice from auditory hypersensitivity-associated seizures. Here we tested the hypothesis that NLX-101 will normalize EEG phenotypes in developing Fmr1 KO mice. METHODS: To test this hypothesis, we examined the effect of NLX-101 on EEG phenotypes in male and female wildtype (WT) and Fmr1 KO mice. Using epidural electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at two ages, postnatal (P) 21 and 30 days, from both auditory and frontal cortices of awake, freely moving mice, following NLX-101 (at 1.8 mg/kg i.p.) or saline administration. RESULTS: Saline-injected Fmr1 KO mice showed increased N1 amplitudes, increased STP and reduced phase locking to auditory gap-in-noise stimuli versus wild-type mice, reproducing previously published EEG phenotypes. An acute injection of NLX-101 did not alter ERP amplitudes at either P21 or P30, but significantly reduces STP at P30. Inter-trial phase clustering was significantly increased in both age groups with NLX-101, indicating improved temporal processing. The differential effects of serotonin modulation on ERP, background power and temporal processing suggest different developmental mechanisms leading to these phenotypes. CONCLUSIONS: These results suggest that NLX-101 could constitute a promising treatment option for targeting post-synaptic 5-HT(1A) receptors to improve auditory temporal processing, which in turn may improve speech and language function in FXS. En ligne : https://dx.doi.org/10.1186/s11689-024-09587-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Acute administration of NLX-101, a Serotonin 1A receptor agonist, improves auditory temporal processing during development in a mouse model of Fragile X Syndrome [texte imprimé] / Xin TAO, Auteur ; Katilynne CROOM, Auteur ; Adrian NEWMAN-TANCREDI, Auteur ; Mark VARNEY, Auteur ; Khaleel A. RAZAK, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Animals  Fragile X Syndrome/physiopathology  Disease Models, Animal  Mice, Knockout  Mice  Fragile X Mental Retardation Protein/genetics  Male  Electroencephalography  Serotonin 5-HT1 Receptor Agonists/pharmacology/administration & dosage  Auditory Perception/drug effects/physiology  Female  Mice, Inbred C57BL  Evoked Potentials, Auditory/drug effects/physiology  5-HT1A receptors  Autism spectrum disorders  Fragile X syndrome  Sensory hypersensitivity  Serotonin  Speech processing  Temporal processing  by Institutional Animal Care and Use Committee at the University of California,  Riverside. Consent for publication: Not applicable. Competing interests: MV &  AN-T are Shareholders in Neurolixis. Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a leading known genetic cause of intellectual disability and autism spectrum disorders (ASD)-associated behaviors. A consistent and debilitating phenotype of FXS is auditory hypersensitivity that may lead to delayed language and high anxiety. Consistent with findings in FXS human studies, the mouse model of FXS, the Fmr1 knock out (KO) mouse, shows auditory hypersensitivity and temporal processing deficits. In electroencephalograph (EEG) recordings from humans and mice, these deficits manifest as increased N1 amplitudes in event-related potentials (ERP), increased gamma band single trial power (STP) and reduced phase locking to rapid temporal modulations of sound. In our previous study, we found that administration of the selective serotonin-1 A (5-HT(1A))receptor biased agonist, NLX-101, protected Fmr1 KO mice from auditory hypersensitivity-associated seizures. Here we tested the hypothesis that NLX-101 will normalize EEG phenotypes in developing Fmr1 KO mice. METHODS: To test this hypothesis, we examined the effect of NLX-101 on EEG phenotypes in male and female wildtype (WT) and Fmr1 KO mice. Using epidural electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at two ages, postnatal (P) 21 and 30 days, from both auditory and frontal cortices of awake, freely moving mice, following NLX-101 (at 1.8 mg/kg i.p.) or saline administration. RESULTS: Saline-injected Fmr1 KO mice showed increased N1 amplitudes, increased STP and reduced phase locking to auditory gap-in-noise stimuli versus wild-type mice, reproducing previously published EEG phenotypes. An acute injection of NLX-101 did not alter ERP amplitudes at either P21 or P30, but significantly reduces STP at P30. Inter-trial phase clustering was significantly increased in both age groups with NLX-101, indicating improved temporal processing. The differential effects of serotonin modulation on ERP, background power and temporal processing suggest different developmental mechanisms leading to these phenotypes. CONCLUSIONS: These results suggest that NLX-101 could constitute a promising treatment option for targeting post-synaptic 5-HT(1A) receptors to improve auditory temporal processing, which in turn may improve speech and language function in FXS. En ligne : https://dx.doi.org/10.1186/s11689-024-09587-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome / Carrie R. JONAK in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome Type de document : texte imprimé Auteurs : Carrie R. JONAK, Auteur ; Ernest V. PEDAPATI, Auteur ; Lauren M. SCHMITT, Auteur ; Samantha A. ASSAD, Auteur ; Manbir S. SANDHU, Auteur ; Lisa DESTEFANO, Auteur ; Lauren ETHRIDGE, Auteur ; Khaleel A. RAZAK, Auteur ; John A. SWEENEY, Auteur ; Devin K. BINDER, Auteur ; Craig A. ERICKSON, Auteur Langues : Anglais (eng) Mots-clés : Animals  Baclofen/pharmacology  Disease Models, Animal  Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/complications/drug therapy  Humans  Male  Mice  Mice, Knockout  Autism  Baclofen  Biomarker  Electroencephalography  Fragile X syndrome  Multielectrode array  in fragile X syndrome held by the Cincinnati Children’s Research Foundation  (CCRF) and licensed out at the discretion of CCRF. CAE is a current consultant to  Impel, Stalicla, and Scioto Bioscience. Index. décimale : PER Périodiques Résumé : 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 GABA(B) selective agonist racemic baclofen (RBAC). RESULTS: In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 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. En ligne : https://dx.doi.org/10.1186/s11689-022-09455-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome [texte imprimé] / Carrie R. JONAK, Auteur ; Ernest V. PEDAPATI, Auteur ; Lauren M. SCHMITT, Auteur ; Samantha A. ASSAD, Auteur ; Manbir S. SANDHU, Auteur ; Lisa DESTEFANO, Auteur ; Lauren ETHRIDGE, Auteur ; Khaleel A. RAZAK, Auteur ; John A. SWEENEY, Auteur ; Devin K. BINDER, Auteur ; Craig A. ERICKSON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Animals  Baclofen/pharmacology  Disease Models, Animal  Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/complications/drug therapy  Humans  Male  Mice  Mice, Knockout  Autism  Baclofen  Biomarker  Electroencephalography  Fragile X syndrome  Multielectrode array  in fragile X syndrome held by the Cincinnati Children’s Research Foundation  (CCRF) and licensed out at the discretion of CCRF. CAE is a current consultant to  Impel, Stalicla, and Scioto Bioscience. Index. décimale : PER Périodiques Résumé : 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 GABA(B) selective agonist racemic baclofen (RBAC). RESULTS: In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 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. En ligne : https://dx.doi.org/10.1186/s11689-022-09455-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome / Katilynne CROOM in Journal of Neurodevelopmental Disorders, 15 (2023)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 15 (2023) Titre : Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome Type de document : texte imprimé Auteurs : Katilynne CROOM, Auteur ; Jeffrey A. RUMSCHLAG, Auteur ; Michael A. ERICKSON, Auteur ; Devin K. BINDER, Auteur ; Khaleel A. RAZAK, Auteur Langues : Anglais (eng) Mots-clés : Humans  Adult  Animals  Mice  Fragile X Syndrome/complications  Cross-Sectional Studies  Time Perception  Disease Models, Animal  Mice, Knockout  Fragile X Mental Retardation Protein/genetics  Autism spectrum disorders  Cerebral cortex  Fragile X syndrome  Language  Neurodevelopment  Sensory hypersensitivity  Speech processing  Temporal processing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. METHODS: In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. RESULTS: We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. CONCLUSIONS: These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD. En ligne : https://dx.doi.org/10.1186/s11689-023-09496-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome [texte imprimé] / Katilynne CROOM, Auteur ; Jeffrey A. RUMSCHLAG, Auteur ; Michael A. ERICKSON, Auteur ; Devin K. BINDER, Auteur ; Khaleel A. RAZAK, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 15 (2023) Mots-clés : Humans  Adult  Animals  Mice  Fragile X Syndrome/complications  Cross-Sectional Studies  Time Perception  Disease Models, Animal  Mice, Knockout  Fragile X Mental Retardation Protein/genetics  Autism spectrum disorders  Cerebral cortex  Fragile X syndrome  Language  Neurodevelopment  Sensory hypersensitivity  Speech processing  Temporal processing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. METHODS: In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. RESULTS: We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. CONCLUSIONS: These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD. En ligne : https://dx.doi.org/10.1186/s11689-023-09496-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Developmental studies in fragile X syndrome / Khaleel A. RAZAK in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Developmental studies in fragile X syndrome Type de document : texte imprimé Auteurs : Khaleel A. RAZAK, Auteur ; Kelli C. DOMINICK, Auteur ; Craig A. ERICKSON, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Disease Models, Animal  Female  Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/genetics  Humans  Infant  Male  Mice  Mice, Knockout  Young Adult Index. décimale : PER Périodiques Résumé : Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual disabilities. Humans with FXS exhibit increased anxiety, sensory hypersensitivity, seizures, repetitive behaviors, cognitive inflexibility, and social behavioral impairments. The main purpose of this review is to summarize developmental studies of FXS in humans and in the mouse model, the Fmr1 knockout mouse. The literature presents considerable evidence that a number of early developmental deficits can be identified and that these early deficits chart a course of altered developmental experience leading to symptoms well characterized in adolescents and adults. Nevertheless, a number of critical issues remain unclear or untested regarding the development of symptomology and underlying mechanisms. First, what is the role of FMRP, the protein product of Fmr1 gene, during different developmental ages? Does the absence of FMRP during early development lead to irreversible changes, or could reintroduction of FMRP or therapeutics aimed at FMRP-interacting proteins/pathways hold promise when provided in adults? These questions have implications for clinical trial designs in terms of optimal treatment windows, but few studies have systematically addressed these issues in preclinical and clinical work. Published studies also point to complex trajectories of symptom development, leading to the conclusion that single developmental time point studies are unlikely to disambiguate effects of genetic mutation from effects of altered developmental experience and compensatory plasticity. We conclude by suggesting a number of experiments needed to address these major gaps in the field. En ligne : https://dx.doi.org/10.1186/s11689-020-09310-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Developmental studies in fragile X syndrome [texte imprimé] / Khaleel A. RAZAK, Auteur ; Kelli C. DOMINICK, Auteur ; Craig A. ERICKSON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Disease Models, Animal  Female  Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/genetics  Humans  Infant  Male  Mice  Mice, Knockout  Young Adult Index. décimale : PER Périodiques Résumé : Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual disabilities. Humans with FXS exhibit increased anxiety, sensory hypersensitivity, seizures, repetitive behaviors, cognitive inflexibility, and social behavioral impairments. The main purpose of this review is to summarize developmental studies of FXS in humans and in the mouse model, the Fmr1 knockout mouse. The literature presents considerable evidence that a number of early developmental deficits can be identified and that these early deficits chart a course of altered developmental experience leading to symptoms well characterized in adolescents and adults. Nevertheless, a number of critical issues remain unclear or untested regarding the development of symptomology and underlying mechanisms. First, what is the role of FMRP, the protein product of Fmr1 gene, during different developmental ages? Does the absence of FMRP during early development lead to irreversible changes, or could reintroduction of FMRP or therapeutics aimed at FMRP-interacting proteins/pathways hold promise when provided in adults? These questions have implications for clinical trial designs in terms of optimal treatment windows, but few studies have systematically addressed these issues in preclinical and clinical work. Published studies also point to complex trajectories of symptom development, leading to the conclusion that single developmental time point studies are unlikely to disambiguate effects of genetic mutation from effects of altered developmental experience and compensatory plasticity. We conclude by suggesting a number of experiments needed to address these major gaps in the field. En ligne : https://dx.doi.org/10.1186/s11689-020-09310-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice / Patricia S. PIRBHOY in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice Type de document : texte imprimé Auteurs : Patricia S. PIRBHOY, Auteur ; Carrie R. JONAK, Auteur ; Rashid SYED, Auteur ; Donovan A. ARGUETA, Auteur ; Pedro A. PEREZ, Auteur ; Mark B. WILEY, Auteur ; Keon HESSAMIAN, Auteur ; Jonathan W. LOVELACE, Auteur ; Khaleel A. RAZAK, Auteur ; Nicholas V. DIPATRIZIO, Auteur ; Iryna M. ETHELL, Auteur ; Devin K. BINDER, Auteur Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder  Endocannabinoids  Fragile X Mental Retardation Protein/genetics  Glycerol  Male  Mice  Mice, Knockout  2-Arachidonoyl-sn-glycerol  Auditory hypersensitivity  Cortical hyperexcitability  Electroencephalography  Endocannabinoid modulation  Gamma-band power Index. décimale : PER Périodiques Résumé : BACKGROUND: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. METHODS: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. RESULTS: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. CONCLUSIONS: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs. En ligne : https://dx.doi.org/10.1186/s11689-021-09394-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice [texte imprimé] / Patricia S. PIRBHOY, Auteur ; Carrie R. JONAK, Auteur ; Rashid SYED, Auteur ; Donovan A. ARGUETA, Auteur ; Pedro A. PEREZ, Auteur ; Mark B. WILEY, Auteur ; Keon HESSAMIAN, Auteur ; Jonathan W. LOVELACE, Auteur ; Khaleel A. RAZAK, Auteur ; Nicholas V. DIPATRIZIO, Auteur ; Iryna M. ETHELL, Auteur ; Devin K. BINDER, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Animals  Autism Spectrum Disorder  Endocannabinoids  Fragile X Mental Retardation Protein/genetics  Glycerol  Male  Mice  Mice, Knockout  2-Arachidonoyl-sn-glycerol  Auditory hypersensitivity  Cortical hyperexcitability  Electroencephalography  Endocannabinoid modulation  Gamma-band power Index. décimale : PER Périodiques Résumé : BACKGROUND: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. METHODS: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. RESULTS: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. CONCLUSIONS: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs. En ligne : https://dx.doi.org/10.1186/s11689-021-09394-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice / Katilynne CROOM in Journal of Neurodevelopmental Disorders, 16 (2024)  

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