Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice

Autor: Keon Hessamian, Carrie R. Jonak, Patricia S Pirbhoy, Jonathan W. Lovelace, Nicholas V. DiPatrizio, Khaleel A. Razak, Rashid Syed, Donovan A Argueta, Mark B Wiley, Iryna M. Ethell, Pedro A. Perez, Devin K. Binder
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Glycerol
Male
medicine.medical_specialty
Elevated plus maze
Autism Spectrum Disorder
Cognitive Neuroscience
Knockout
Intellectual and Developmental Disabilities (IDD)
Sensory system
Neurosciences. Biological psychiatry. Neuropsychiatry
Electroencephalography
Auditory cortex
Basic Behavioral and Social Science
Open field
Pathology and Forensic Medicine
Cortical hyperexcitability
Fragile X Mental Retardation Protein
Mice
Rare Diseases
Internal medicine
Behavioral and Social Science
Medicine
Animals
Psychology
Auditory hypersensitivity
Mice
Knockout
Pediatric
2-Arachidonoyl-sn-glycerol
medicine.diagnostic_test
business.industry
Research
Neurosciences
medicine.disease
FMR1
Endocannabinoid system
Brain Disorders
Fragile X syndrome
Endocrinology
Mental Health
Fragile X Syndrome
Endocannabinoid modulation
Pediatrics
Perinatology and Child Health
Gamma-band power
Neurology (clinical)
business
Endocannabinoids
RC321-571
Zdroj: Journal of Neurodevelopmental Disorders, Vol 13, Iss 1, Pp 1-19 (2021)
Journal of neurodevelopmental disorders, vol 13, iss 1
Journal of Neurodevelopmental Disorders
ISSN: 1866-1955
1866-1947
Popis: 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.
Databáze: OpenAIRE
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