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

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

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)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice Type de document : texte imprimé Auteurs : Katilynne CROOM, Auteur ; Jeffrey A. RUMSCHLAG, Auteur ; Michael A. ERICKSON, Auteur ; Devin BINDER, Auteur ; Khaleel A. RAZAK, Auteur Langues : Anglais (eng) Mots-clés : Animals  Fragile X Syndrome/physiopathology  Female  Male  Disease Models, Animal  Mice  Sex Characteristics  Mice, Knockout  Evoked Potentials, Auditory/physiology  Fragile X Mental Retardation Protein/genetics  Auditory Perception/physiology  Autism Spectrum Disorder/physiopathology  Auditory Cortex/physiopathology  Mice, Inbred C57BL  Autism Spectrum Disorders  Frontal Cortex  Hypersensitivity  Language Impairments  Neurodevelopment  Sensory Processing Disorders  Temporal Processing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. METHODS: To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. RESULTS: The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. CONCLUSIONS: These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS. En ligne : https://dx.doi.org/10.1186/s11689-024-09539-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice [texte imprimé] / Katilynne CROOM, Auteur ; Jeffrey A. RUMSCHLAG, Auteur ; Michael A. ERICKSON, Auteur ; Devin BINDER, Auteur ; Khaleel A. RAZAK, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Animals  Fragile X Syndrome/physiopathology  Female  Male  Disease Models, Animal  Mice  Sex Characteristics  Mice, Knockout  Evoked Potentials, Auditory/physiology  Fragile X Mental Retardation Protein/genetics  Auditory Perception/physiology  Autism Spectrum Disorder/physiopathology  Auditory Cortex/physiopathology  Mice, Inbred C57BL  Autism Spectrum Disorders  Frontal Cortex  Hypersensitivity  Language Impairments  Neurodevelopment  Sensory Processing Disorders  Temporal Processing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. METHODS: To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. RESULTS: The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. CONCLUSIONS: These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS. En ligne : https://dx.doi.org/10.1186/s11689-024-09539-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

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