Abstract
BackgroundIndividuals 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.MethodsTo 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.ResultsLipidomic 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.ConclusionsOverall, 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.
Highlights
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
In the current study, we examined whether increasing the levels of the eCB receptor ligand, 2-AG, normalizes neural correlates of auditory hypersensitivity and behavioral deficits in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice
JZL‐184 treatment increases levels of 2‐AG in the cortex of Fragile X mental retardation 1 (Fmr1) KO and WT mice In the current study, we examined whether increasing the levels of the eCB receptor ligand, 2-AG, normalizes neural correlates of auditory hypersensitivity in Fmr1 KO mice
Summary
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. Similar EEG findings are observed in rodent models of FXS, the Fmr knock-out (KO) rat [26] and mouse [27,28,29,30], where both developing [29, 30] and adult [27, 28] Fmr KO mice exhibit increased gammaband power in the auditory and frontal cortex compared to wild-type (WT) counterparts The reproducibility of these neurophysiological measures in replicate studies and FXS rodent models provides a unique opportunity to assess the efficacy of pharmacological interventions. EEG assessment was used to test the efficacy of an endocannabinoid (eCB)-positive modulator, JZL184, which inhibits monoacylglycerol lipase (MAGL) [31, 32], a hydrolase involved in 2-arachidonoyl-sn-glycerol (2-AG) degradation [33], as a potential therapeutic for FXS
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