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

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

---

1 (1 - 2 / 2) Par page : 25 50 100 200